Статті в журналах з теми "Telomere Position Effect"
Щоб переглянути інші типи публікацій з цієї теми, перейдіть за посиланням: Telomere Position Effect.
Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями
Ознайомтеся з топ-50 статей у журналах для дослідження на тему "Telomere Position Effect".
Біля кожної праці в переліку літератури доступна кнопка «Додати до бібліографії». Скористайтеся нею – і ми автоматично оформимо бібліографічне посилання на обрану працю в потрібному вам стилі цитування: APA, MLA, «Гарвард», «Чикаго», «Ванкувер» тощо.
Також ви можете завантажити повний текст наукової публікації у форматі «.pdf» та прочитати онлайн анотацію до роботи, якщо відповідні параметри наявні в метаданих.
Переглядайте статті в журналах для різних дисциплін та оформлюйте правильно вашу бібліографію.
1
Dahlén, Maria, Per Sunnerhagen, and Teresa S. F. Wang. "Replication Proteins Influence the Maintenance of Telomere Length and Telomerase Protein Stability." Molecular and Cellular Biology 23, no. 9 (May 1, 2003): 3031–42. http://dx.doi.org/10.1128/mcb.23.9.3031-3042.2003.
Анотація:
ABSTRACT We investigated the effects of fission yeast replication genes on telomere length maintenance and identified 20 mutant alleles that confer lengthening or shortening of telomeres. The telomere elongation was telomerase dependent in the replication mutants analyzed. Furthermore, the telomerase catalytic subunit, Trt1, and the principal initiation and lagging-strand synthesis DNA polymerase, Polα, were reciprocally coimmunoprecipitated, indicating these proteins physically coexist as a complex in vivo. In a polα mutant that exhibited abnormal telomere lengthening and slightly reduced telomere position effect, the cellular level of the Trt1 protein was significantly lower and the coimmunoprecipitation of Trt1 and Polα was severely compromised compared to those in the wild-type polα cells. Interestingly, ectopic expression of wild-type polα in this polα mutant restored the cellular Trt1 protein to the wild-type level and shortened the telomeres to near-wild-type length. These results suggest that there is a close physical relationship between the replication and telomerase complexes. Thus, mutation of a component of the replication complex can affect the telomeric complex in maintaining both telomere length equilibrium and telomerase protein stability.
2
de Bruin, Derik, Sara M. Kantrow, Rachel A. Liberatore, and Virginia A. Zakian. "Telomere Folding Is Required for the Stable Maintenance of Telomere Position Effects in Yeast." Molecular and Cellular Biology 20, no. 21 (November 1, 2000): 7991–8000. http://dx.doi.org/10.1128/mcb.20.21.7991-8000.2000.
Анотація:
ABSTRACT Yeast telomeres reversibly repress the transcription of adjacent genes, a phenomenon called telomere position effect (TPE). TPE is thought to result from Rap1 and Sir protein-mediated spreading of heterochromatin-like structures from the telomeric DNA inwards. Because Rap1p is associated with subtelomeric chromatin as well as with telomeric DNA, yeast telomeres are proposed to form fold-back or looped structures. TPE can be eliminated in trans by deletingSIR genes or in cis by transcribing through the C1–3A/TG1–3 tract of a telomere. We show that the promoter of a telomere-linked URA3 gene was inaccessible to restriction enzymes and that accessibility increased both in a sir3 strain and upon telomere transcription. We also show that subtelomeric chromatin was hypoacetylated at histone H3 and at each of the four acetylatable lysines in histone H4 and that histone acetylation increased both in a sir3 strain and when the telomere was transcribed. When transcription through the telomeric tract occurred in G1-arrested cells, TPE was lost, demonstrating that activation of a silenced telomeric gene can occur in the absence of DNA replication. The loss of TPE that accompanied telomere transcription resulted in the rapid and efficient loss of subtelomeric Rap1p. We propose that telomere transcription disrupts core heterochromatin by eliminating Rap1p-mediated telomere looping. This interpretation suggests that telomere looping is critical for maintaining TPE.
3
Park, Yangsuk, and Arthur J. Lustig. "Telomere Structure Regulates the Heritability of Repressed Subtelomeric Chromatin in Saccharomyces cerevisiae." Genetics 154, no. 2 (February 1, 2000): 587–98. http://dx.doi.org/10.1093/genetics/154.2.587.
Анотація:
Abstract Telomeres, the protein-DNA structures present at the termini of linear chromosomes, are capable of conferring a reversible repression of Pol II- and Pol III-transcribed genes positioned in adjacent subtelomeric regions. This phenomenon, termed telomeric silencing, is likely to be the consequence of a more global telomere position effect at the level of chromatin structure. To understand the role of telomere structure in this position effect, we have developed an assay to distinguish between the heritability of transcriptionally repressed and derepressed states in yeast. We have previously demonstrated that an elongated telomeric tract leads to hyperrepression of telomere-adjacent genes. We show here that the predominant effect of elongated telomeres is to increase the inheritance of the repressed state in cis. Interestingly, the presence of elongated telomeres overcomes the partial requirement of yCAF-1 in silencing. We propose that the formation of a specific telomeric structure is necessary for the heritability of repressed subtelomeric chromatin.
4
Yu, Eun Young, Olga Steinberg-Neifach, Alain T. Dandjinou, Frances Kang, Ashby J. Morrison, Xuetong Shen, and Neal F. Lue. "Regulation of Telomere Structure and Functions by Subunits of the INO80 Chromatin Remodeling Complex." Molecular and Cellular Biology 27, no. 16 (June 11, 2007): 5639–49. http://dx.doi.org/10.1128/mcb.00418-07.
Анотація:
ABSTRACT ATP-dependent chromatin remodeling complexes have been implicated in the regulation of transcription, replication, and more recently DNA double-strand break repair. Here we report that the Ies3p subunit of the Saccharomyces cerevisiae INO80 chromatin remodeling complex interacts with a conserved tetratricopeptide repeat domain of the telomerase protein Est1p. Deletion of IES3 and some other subunits of the complex induced telomere elongation and altered telomere position effect. In telomerase-negative mutants, loss of Ies3p delayed the emergence of recombinational survivors and stimulated the formation of extrachromosomal telomeric circles in survivors. Deletion of IES3 also resulted in heightened levels of telomere-telomere fusions in telomerase-deficient strains. In addition, a delay in survivor formation was observed in an Arp8p-deficient mutant. Because Arp8p is required for the chromatin remodeling activity of the INO80 complex, the complex may promote recombinational telomere maintenance by altering chromatin structure. Consistent with this notion, we observed preferential localization of multiple subunits of the INO80 complex to telomeres. Our results reveal novel functions for a subunit of the telomerase complex and the INO80 chromatin remodeling complex.
5
Runge, K. W., and V. A. Zakian. "TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae." Molecular and Cellular Biology 16, no. 6 (June 1996): 3094–105. http://dx.doi.org/10.1128/mcb.16.6.3094.
Анотація:
The DNA-protein complexes at the ends of linear eukaryotic chromosomes are called the telomeres. In Saccharomyces cerevisiae, telomeric DNA consists of a variable length of the short repeated sequence C1-3A. The length of yeast telomeres can be altered by mutation, by changing the levels of telomere binding proteins, or by increasing the amount of C1-3A DNA sequences. Cells bearing the tel1-1 or tel2-1 mutations, known previously to have short telomeres, did not respond to perturbations that caused telomere lengthening in wild-type cells. The transcription of genes placed near yeast telomeres is reversibly repressed, a phenomenon called the telomere position effect. The tel2-1 mutation reduced the position effect but did not affect transcriptional repression at the silent mating type cassettes, HMRa and HML alpha. The TEL2 gene was cloned, sequenced, and disrupted. Cells lacking TEL2 function died, with some cells arresting as large cells with three or four small protrusions or "blebs."
6
Mason, James M., Alexander Y. Konev, Mikhail D. Golubovsky, and Harald Biessmann. "Cis- andtrans-acting Influences on Telomeric Position Effect inDrosophila melanogasterDetected With a Subterminal Transgene." Genetics 163, no. 3 (March 1, 2003): 917–30. http://dx.doi.org/10.1093/genetics/163.3.917.
Анотація:
AbstractOne model of telomeric position effect (TPE) in Drosophila melanogaster proposes that reporter genes in the vicinity of telomeres are repressed by subterminal telomere-associated sequences (TAS) and that variegation of these genes is the result of competition between the repressive effects of TAS and the stimulating effects of promoters in the terminal HeT-A transposon array. The data presented here support this model, but also suggest that TPE is more complex. Activity of a telomeric white reporter gene increases in response to deletion of some or all of the TAS on the homolog. Only transgenes next to fairly long HeT-A arrays respond to this trans-interaction. HeT-A arrays of 6-18 kb respond by increasing the number of dark spots on the eye, while longer arrays increase the background eye color or increase the number of spots sufficiently to cause them to merge. Thus, expression of a subtelomeric reporter gene is influenced by the telomere structure in cis and trans. We propose that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as TPE. In the wild-type telomere TAS may play an important role in controlling telomere elongation by repressing HeT-A promoter activity. Modulation of this repression by the homolog may thus regulate telomere elongation.
7
Denisenko, Oleg, and Karol Bomsztyk. "Yeast hnRNP K-Like Genes Are Involved in Regulation of the Telomeric Position Effect and Telomere Length." Molecular and Cellular Biology 22, no. 1 (January 1, 2002): 286–97. http://dx.doi.org/10.1128/mcb.22.1.286-297.2002.
Анотація:
ABSTRACT Mammalian heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA- and DNA-binding protein implicated in the regulation of gene expression processes. To better understand its function, we studied two Saccharomyces cerevisiae homologues of the human hnRNP K, PBP2 and HEK2 (heterogeneous nuclear RNP K-like gene). pbp2Δ and hek2Δ mutations inhibited expression of a marker gene that was inserted near telomere but not at internal chromosomal locations. The telomere proximal to the ectopic marker gene became longer, while most of the other telomeres were not altered in the double mutant cells. We provide evidence that telomere elongation might be the primary event that causes enhanced silencing of an adjacent reporter gene. The telomere lengthening could, in part, be explained by the inhibitory effect of hek2Δ mutation on the telomeric rapid deletion pathway. Hek2p was detected in a complex with chromosome regions proximal to the affected telomere, suggesting a direct involvement of this protein in telomere maintenance. These results identify a role for hnRNP K-like genes in the structural and functional organization of telomeric chromatin in yeast.
8
Biessmann, Harald, Sudha Prasad, Marika F. Walter, and James M. Mason. "Euchromatic and heterochromatic domains at Drosophila telomeres." Biochemistry and Cell Biology 83, no. 4 (August 1, 2005): 477–85. http://dx.doi.org/10.1139/o05-053.
Анотація:
Noncoding repetitive sequences make up a large portion of eukaryotic genomes, but their function is not well understood. Large blocks of repetitive DNA-forming heterochromatin around the centromeres are required for this region to function properly, but are difficult to analyze. The smaller regions of heterochromatin at the telomeres provide an opportunity to study their DNA and protein composition. Drosophila telomere length is maintained through the targeted transposition of specific non-long terminal repeat retrotransposons to chromosome ends, where they form long tandem arrays. A subterminal telomere-associated sequence (TAS) lies immediately proximal to the terminal-retrotransposon array. Here, we review the experimental support for the heterochromatic features of Drosophila telomeres, and provide evidence that telomeric regions contain 2 distinct chromatin subdomains: TAS, which exhibits features that resemble beta heterochromatin; and the terminal array of retrotransposons, which appears euchromatic. This organization is significantly different from the telomeric organization of other eukaryotes, where the terminal telomerase-generated repeats are often folded in a t-loop structure and become part of the heterochromatin protein complex.Key words: Drosophila, telomere, gene silencing, position effect, heterochromatin.
9
Suzuki, Y., and M. Nishizawa. "The yeast GAL11 protein is involved in regulation of the structure and the position effect of telomeres." Molecular and Cellular Biology 14, no. 6 (June 1994): 3791–99. http://dx.doi.org/10.1128/mcb.14.6.3791-3799.1994.
Анотація:
GAL11 is an auxiliary transcription factor that functions either positively or negatively, depending on the structure of the target promoters and the combination of DNA-bound activators. In this report, we demonstrate that a gal11 delta mutation caused a decrease in the length of the telomere C1-3A tract, a derepression of URA3 when it is placed next to telomere, and an increase in accessibility of the telomeric region to dam methylase, indicating that GAL11 is involved in the regulation of the structure and the position effect of telomeres. The defective position effect in a gal11 delta strain was suppressed by overproduction of SIR3, whereas overexpression of GAL11 failed to restore the telomere position effect in a sir3 delta strain. Hyperproduced GAL11 could partially suppress the defect in silencing at HMR in a sir1 delta mutant but not that in a sir3 delta mutant, suggesting that GAL11 can replace SIR1 function partly in the silencing of HMR. Overproduced SIR3 also could restore silencing at HMR in sir1 delta cells. In contrast, SIR1 in a multicopy plasmid relieved the telomere position effect, especially in a gal11 delta mutant. Since chromatin structure is thought to play a major role in the silencing at both the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by modulating the chromatin structure.
10
Suzuki, Y., and M. Nishizawa. "The yeast GAL11 protein is involved in regulation of the structure and the position effect of telomeres." Molecular and Cellular Biology 14, no. 6 (June 1994): 3791–99. http://dx.doi.org/10.1128/mcb.14.6.3791.
Анотація:
GAL11 is an auxiliary transcription factor that functions either positively or negatively, depending on the structure of the target promoters and the combination of DNA-bound activators. In this report, we demonstrate that a gal11 delta mutation caused a decrease in the length of the telomere C1-3A tract, a derepression of URA3 when it is placed next to telomere, and an increase in accessibility of the telomeric region to dam methylase, indicating that GAL11 is involved in the regulation of the structure and the position effect of telomeres. The defective position effect in a gal11 delta strain was suppressed by overproduction of SIR3, whereas overexpression of GAL11 failed to restore the telomere position effect in a sir3 delta strain. Hyperproduced GAL11 could partially suppress the defect in silencing at HMR in a sir1 delta mutant but not that in a sir3 delta mutant, suggesting that GAL11 can replace SIR1 function partly in the silencing of HMR. Overproduced SIR3 also could restore silencing at HMR in sir1 delta cells. In contrast, SIR1 in a multicopy plasmid relieved the telomere position effect, especially in a gal11 delta mutant. Since chromatin structure is thought to play a major role in the silencing at both the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by the HM loci and telomeres, GAL11 is likely to participate in the regional regulation of transcription by modulating the chromatin structure.
11
Kulkarni, Avanti, Oliver Zschenker, Gloria Reynolds, Douglas Miller, and John P. Murnane. "Effect of Telomere Proximity on Telomere Position Effect, Chromosome Healing, and Sensitivity to DNA Double-Strand Breaks in a Human Tumor Cell Line." Molecular and Cellular Biology 30, no. 3 (November 23, 2009): 578–89. http://dx.doi.org/10.1128/mcb.01137-09.
Анотація:
ABSTRACT The ends of chromosomes, called telomeres, are composed of a DNA repeat sequence and associated proteins, which prevent DNA degradation and chromosome fusion. We have previously used plasmid sequences integrated adjacent to a telomere to demonstrate that mammalian telomeres suppress gene expression, called telomere position effect (TPE). We have also shown that subtelomeric regions are highly sensitive to double-strand breaks, leading to chromosome instability, and that this instability can be prevented by the addition of a new telomere to the break, a process called chromosome healing. We have now targeted the same plasmid sequences to a site 100 kb from a telomere in a human carcinoma cell line to address the effect of telomere proximity on telomere position effect, chromosome healing, and sensitivity to double-strand breaks. The results demonstrate a substantial decrease in TPE 100 kb from the telomere, demonstrating that TPE is very limited in range. Chromosome healing was also diminished 100 kb from the telomere, consistent with our model that chromosome healing serves as a repair process for restoring lost telomeres. Conversely, the region 100 kb from the telomere was highly sensitive to double-strand breaks, demonstrating that the sensitive region is a relatively large target for ionizing radiation-induced chromosome instability.
12
Pedram, Mehrdad, Carl N. Sprung, Qing Gao, Anthony W. I. Lo, Gloria E. Reynolds, and John P. Murnane. "Telomere Position Effect and Silencing of Transgenes near Telomeres in the Mouse." Molecular and Cellular Biology 26, no. 5 (March 1, 2006): 1865–78. http://dx.doi.org/10.1128/mcb.26.5.1865-1878.2006.
Анотація:
ABSTRACT Reversible transcriptional silencing of genes located near telomeres, termed the telomere position effect (TPE), is well characterized in Saccharomyces cerevisiae. TPE has also been observed in human tumor cell lines, but its function remains unknown. To investigate TPE in normal mammalian cells, we developed clones of mouse embryonic stem (ES) cells that contain single-copy marker genes integrated adjacent to different telomeres. Analysis of these telomeric transgenes demonstrated that they were expressed at very low levels compared to the same transgenes integrated at interstitial sites. Similar to the situation in yeast, but in contrast to studies with human tumor cell lines, TPE in mouse ES cells was not reversed with trichostatin A. Prolonged culturing without selection resulted in extensive DNA methylation and complete silencing of telomeric transgenes, which could be reversed by treatment with 5-azacytidine. Thus, complete silencing of the telomeric transgenes appears to involve a two-step process in which the initial repression is reinforced by DNA methylation. Extensive methylation of the telomeric transgenes was also observed in various tissues and embryonic fibroblasts isolated from transgenic mice. In contrast, telomeric transgenes were not silenced in ES cell lines isolated from 3-day-old preimplantation embryos, consistent with the hypothesis that TPE plays a role in the development of the embryo.
13
Huang, H., A. Kahana, D. E. Gottschling, L. Prakash, and S. W. Liebman. "The ubiquitin-conjugating enzyme Rad6 (Ubc2) is required for silencing in Saccharomyces cerevisiae." Molecular and Cellular Biology 17, no. 11 (November 1997): 6693–99. http://dx.doi.org/10.1128/mcb.17.11.6693.
Анотація:
It has been previously shown that genes transcribed by RNA polymerase II (RNAP II) are subject to position effect variegation when located near yeast telomeres. This telomere position effect requires a number of gene products that are also required for silencing at the HML and HMR loci. Here, we show that a null mutation of the DNA repair gene RAD6 reduces silencing of the HM loci and lowers the mating efficiency of MATa strains. Likewise, rad6-delta reduces silencing of the telomere-located RNAP II-transcribed genes URA3 and ADE2. We also show that the RNAP III-transcribed tyrosyl tRNA gene, SUP4-o, is subject to position effect variegation when located near a telomere and that this silencing requires the RAD6 and SIR genes. Neither of the two known Rad6 binding factors, Rad18 and Ubr1, is required for telomeric silencing. Since Ubrl is the recognition component of the N-end rule-dependent protein degradation pathway, this suggests that N-end rule-dependent protein degradation is not involved in telomeric silencing. Telomeric silencing requires the amino terminus of Rad6. Two rad6 point mutations, rad6(C88A) and rad6(C88S), which are defective in ubiquitin-conjugating activity fail to complement the silencing defect, indicating that the ubiquitin-conjugating activity of RAD6 is essential for full telomeric silencing.
14
Bourns, Brenda D., Mary Kate Alexander, Andrew M. Smith, and Virginia A. Zakian. "Sir Proteins, Rif Proteins, and Cdc13p BindSaccharomyces Telomeres In Vivo." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5600–5608. http://dx.doi.org/10.1128/mcb.18.9.5600.
Анотація:
ABSTRACT Although a surprisingly large number of genes affect yeast telomeres, in most cases it is not known if their products act directly or indirectly. We describe a one-hybrid assay for telomere binding proteins and use it to establish that six proteins that affect telomere structure or function but which had not been shown previously to bind telomeres in vivo are indeed telomere binding proteins. A promoter-defective allele of HIS3 was placed adjacent to a chromosomal telomere. Candidate proteins fused to a transcriptional activation domain were tested for the ability to activate transcription of the telomere-linked HIS3 gene. Using this system, Rif1p, Rif2p, Sir2p, Sir3p, Sir4p, and Cdc13p were found to be in vivo telomere binding proteins. None of the proteins activated the same reporter gene when it was at an internal site on the chromosome. Moreover, Cdc13p did not activate the reporter gene when it was adjacent to an internal tract of telomeric sequence, indicating that Cdc13p binding was telomere limited in vivo. The amino-terminal 20% of Cdc13p was sufficient to target Cdc13p to a telomere, suggesting that its DNA binding domain was within this portion of the protein. Rap1p, Rif1p, Rif2p, Sir4p, and Cdc13p activated the telomeric reporter gene in a strain lacking Sir3p, which is essential for telomere position effect (TPE). Thus, the telomeric association of these proteins did not require any of the chromatin features necessary for TPE. The data support models in which the telomere acts as an initiation site for TPE by recruiting silencing proteins to the chromosome end.
15
Ferreira, Helder C., Benjamin D. Towbin, Thibaud Jegou, and Susan M. Gasser. "The shelterin protein POT-1 anchors Caenorhabditis elegans telomeres through SUN-1 at the nuclear periphery." Journal of Cell Biology 203, no. 5 (December 2, 2013): 727–35. http://dx.doi.org/10.1083/jcb.201307181.
Анотація:
Telomeres are specialized protein–DNA structures that protect chromosome ends. In budding yeast, telomeres form clusters at the nuclear periphery. By imaging telomeres in embryos of the metazoan Caenorhabditis elegans, we found that telomeres clustered only in strains that had activated an alternative telomere maintenance pathway (ALT). Moreover, as in yeast, the unclustered telomeres in wild-type embryos were located near the nuclear envelope (NE). This bias for perinuclear localization increased during embryogenesis and persisted in differentiated cells. Telomere position in early embryos required the NE protein SUN-1, the single-strand binding protein POT-1, and the small ubiquitin-like modifier (SUMO) ligase GEI-17. However, in postmitotic larval cells, none of these factors individually were required for telomere anchoring, which suggests that additional mechanisms anchor in late development. Importantly, targeted POT-1 was sufficient to anchor chromatin to the NE in a SUN-1–dependent manner, arguing that its effect at telomeres is direct. This high-resolution description of telomere position within C. elegans extends our understanding of telomere organization in eukaryotes.
16
Zhang, Ning, Yanhui Li, Tsung-Po Lai, Jerry W. Shay, and Gaudenz Danuser. "Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells." Chromosoma 130, no. 1 (February 8, 2021): 61–73. http://dx.doi.org/10.1007/s00412-020-00747-4.
Анотація:
AbstractTelomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1–10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.
17
Frydrychova, Radmila Capkova, Harald Biessmann, Alexander Y. Konev, Mikhail D. Golubovsky, Jessica Johnson, Trevor K. Archer, and James M. Mason. "Transcriptional Activity of the Telomeric Retrotransposon HeT-A in Drosophila melanogaster Is Stimulated as a Consequence of Subterminal Deficiencies at Homologous and Nonhomologous Telomeres." Molecular and Cellular Biology 27, no. 13 (April 30, 2007): 4991–5001. http://dx.doi.org/10.1128/mcb.00515-07.
Анотація:
ABSTRACT Drosophila melanogaster telomeres have two DNA domains: a terminal array of retrotransposons and a subterminal repetitive telomere-associated sequence (TAS), a source of telomere position effect (TPE). We reported previously that deletion of the 2L TAS array leads to dominant suppression of TPE by stimulating in trans expression of a telomeric transgene. Here, we compared the transcript activities of a w transgene inserted between the retrotransposon and TAS arrays at the 2L telomere in genotypes with different lengths of the 2L TAS. In contrast to individuals bearing a wild-type 2L homologue, flies with a TAS deficiency showed a significant increase in the level of telomeric w transcript during development, especially in pupae. Moreover, we identified a read-through w transcript initiated from a retrotransposon promoter in the terminal array. Read-through transcript levels also significantly increased with the presence of a 2L TAS deficiency in trans, indicating a stimulating force of the TAS deficiency on retrotransposon promoter activity. The read-through transcript contributes to total w transcript, although most w transcript originates at the w promoter. While silencing of transgenes in nonhomologous telomeres is suppressed by 2L TAS deficiencies, suggesting a global effect, the overall level of HeT-A transcripts is not increased under similar conditions.
18
Batista, Luis, Franklin Zhong, Sharon A. Savage, and Steven Artandi. "TIN2 Mutations In Dyskeratosis Congenita Cause Telomere Shortening In Induced Pluripotent Stem Cells Through Potent Dominant Negative Inhibition Of Telomerase." Blood 122, no. 21 (November 15, 2013): 590. http://dx.doi.org/10.1182/blood.v122.21.590.590.
Анотація:
Abstract Dyskeratosis congenita (DC) is a bone marrow failure syndrome characterized by widespread defects in diverse tissues and a strong predisposition to cancer. DC is caused by germline mutations in genes controlling maintenance of telomeres, nucleoprotein caps that protect chromosome ends. Mutations in components of the telomerase enzyme comprise a large share of cases, including in TERT, TERC, dyskerin, TCAB1, NOP10 and NHP2. These mutations compromise telomerase function leading to telomere shortening, which in turn impairs stem cell function. We previously created patient-derived iPS cells from patients with mutations in TERT, dyskerin or TCAB1 and analyzed these cells to understand the biochemical defects in the telomerase pathway. In each case we found a unique mechanism underlying these telomerase defects, including: reduced catalytic function (TERT mutations), impaired telomerase assembly (dyskerin mutations) and mislocalization of the enzyme to nucleoli (TCAB1 mutations). A six-member protein complex – shelterin - is essential for proper function of telomeres. Despite the critical importance of shelterin proteins in telomere regulation, only a single telomere binding protein – TIN2 – is mutated in DC. However, how these mutations compromise telomere maintenance remains poorly understood. TIN2 mutations occur in a common, autosomal dominant form of DC, presenting in early life, with particularly severe clinical manifestations and poor outcomes. Mutations in the TIN2 gene are clustered in exon 6a, which corresponds to a protein domain of unknown function. To understand how TIN2 mutations impair telomere maintenance and cause DC, we reprogrammed fibroblasts from patients with TIN2 mutations to iPS cells. We succeeded in generating pluripotent iPS cells from a patient with a frame shift mutation at position 284 of the protein. TIN2-mutant iPS cells expressed all the markers of wild-type iPS cells and human ES cells and could be differentiated to all three germ cell layers in culture. With reprogramming from fibroblasts to iPS cells, telomerase is upregulated and causes telomere elongation in wild-type cells. In analyzing telomeres from TIN2-mutant iPS cells, we found that telomere elongation was abrogated. Instead of telomere elongation, TIN2-mutant iPS cells showed telomere shortening with reprogramming and during passage in cell culture. After extended cell passage, TIN2-mutant iPS cells lost the ability to self-renew and differentiated, concomitant with the activation of the telomere surveillance checkpoint p53. To better understand how TIN2 mutant proteins interfere with telomere maintenance, we overexpressed GFP, wild-type TIN2, or TIN2 truncation mutants from DC patients into human, telomerase-positive cancer cells. Genomic DNA was collected from these cells during passage and analyzed for telomere lengths by Southern blot. Expression of GFP or wild-type TIN2 had no effect on telomere lengths, which were stably maintained during the experiment. In marked contrast, expression of the TIN2 truncation mutants from DC patients led to progressive and dramatic telomere shortening with cell passage. Together, these data in patient-derived iPS cells and in human cancer cells suggest that TIN2 mutants inhibit the action of telomerase at telomeres. These results constitute a new molecular mechanism at play in DC and yield new insight into one of the most common forms of DC. Disclosures: No relevant conflicts of interest to declare.
19
Huang, Y. J., R. Stoffel, H. Tobler, and F. Mueller. "A newly formed telomere in Ascaris suum does not exert a telomere position effect on a nearby gene." Molecular and Cellular Biology 16, no. 1 (January 1996): 130–34. http://dx.doi.org/10.1128/mcb.16.1.130.
Анотація:
During the process of chromatin diminution in Ascaris suum (formerly named Ascaris lumbricoides var. suum), developmentally regulated chromosomal fragmentation and new telomere addition occur within specific chromosomal breakage regions (CBRs). The DNA sequences flanking one of these CBRs (CBR-1) were analyzed, and two protein-encoding genes were found on either side. The noneliminated gene, agp-1, whose AUG start codon is located within approximately 2 kb of the boundary of CBR-1, encodes a putative GTP-binding protein which is structurally related to eukaryotic and prokaryotic elongation factors. Northern (RNA) blot analyses revealed that transcripts of this gene are present at all developmental stages, suggesting that the massive chromosomal rearrangements associated with the process of chromatin diminution have no influence on agp-1 expression. This demonstrates that addition of new telomeres in CBR-1 does not result in a telomeric position effect, a phenomenon previously described in Saccharomyces cerevisiae.
20
Baur, J. A. "Telomere Position Effect in Human Cells." Science 292, no. 5524 (June 15, 2001): 2075–77. http://dx.doi.org/10.1126/science.1062329.
21
Wiley, E. A., and V. A. Zakian. "Extra telomeres, but not internal tracts of telomeric DNA, reduce transcriptional repression at Saccharomyces telomeres." Genetics 139, no. 1 (January 1, 1995): 67–79. http://dx.doi.org/10.1093/genetics/139.1.67.
Анотація:
Abstract Yeast telomeric DNA is assembled into a nonnucleosomal chromatin structure known as the telosome, which is thought to influence the transcriptional repression of genes placed in its vicinity, a phenomenon called telomere position effect (TPE). The product of the RAP1 gene, Rap1p, is a component of the telosome. We show that the fraction of cells exhibiting TPE can be substantially reduced by expressing large amounts of a deletion derivative of Rap1p that is unable to bind DNA, called Rap1 delta BBp, or by introducing extra telomeres on a linear plasmid, presumably because both compete in trans with telomeric chromatin for factor(s) important for TPE. This reduction in TPE, observed in three different strains, was demonstrated for two different genes, each assayed at a different telomere. In contrast, the addition of internal tracts of telomeric DNA on a circular plasmid had very little effect on TPE. The product of the SIR3 gene, Sir3p, appears to be limiting for TPE. Overexpression of Sir3p completely suppressed the reduction in TPE observed with expression of Rap1 delta BBp, but did not restore high levels of TPE to cells with extra telomeres. These results suggest that extra telomeres must titrate a factor other than Sir3p that is important for TPE. These results also provide evidence for a terminus-specific binding factor that is a factor with a higher affinity for DNA termini than for nonterminal tracts of telomeric DNA and indicate that this factor is important for TPE.
22
Oikemus, S. R. "Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect." Genes & Development 18, no. 15 (August 1, 2004): 1850–61. http://dx.doi.org/10.1101/gad.1202504.
23
Scaria, George, Trevor Argall, Shyam S. Jose, Laura Bendzick, and Dan S. Kaufman. "Use of Human Pluripotent Stem Cells to Model the Hematopoietic Defect and Repair of Human Telomerase Deficiency." Blood 126, no. 23 (December 3, 2015): 1212. http://dx.doi.org/10.1182/blood.v126.23.1212.1212.
Анотація:
Abstract Telomeres are repetitive DNA protein structures that cap the ends of chromosomes, protect chromosome ends from degradation and fusion, and are essential for maintenance of genomic integrity. Telomere length has been shown to gradually shorten over time as cells divide. When telomeres become critically short, the cells enter a state of senescence. As such, telomere shortening has been implicated in accelerated aging. Defects in telomerase function have been associated with the development of bone marrow failure. Patients with inherited mutations in telomerase components have significantly shortened telomere lengths and reductions in telomere length have been associated with a worse prognosis in myelodysplastic syndrome (MDS) and Aplastic anemia (AA). We have isolated fibroblasts from patients with a novel mutation in the telomerase RNA component (TERC), a 6 nucleotide in frame duplication at position +334, which results in bone marrow failure. We have derived several lines of human induced pluripotent stem cells (iPSCs) from these patients. We have demonstrated that these telomerase-deficient iPSCs appropriately express markers of pluripotency: Oct4, Sox2, SSEA4, and Nanog. Using quantitative real time PCR, we were able to measure the average telomere length as a T/S ratio of kilobases of telomere length per genome. We have determined that reprogramming results in significant increase in telomere length of control fibroblasts. However despite the typical induction of endogenous TERT expression during reprograming in our telomerase-deficient iPSCs, these TERC-mutant iPSCs did not demonstrate significant telomere elongation. We found telomerase-deficient fibroblasts have telomere lengths of 130-150kb/diploid genome compared to normal human fibroblasts with telomeres of ~250kb/diploid genome. After reprogramming, the iPSCs generated from wild type fibroblasts can have markedly increased telomere lengths to as high as 2000kb/diploid genome. The telomere lengths in TERC-mutant iPSCs from two different patients are less than 300kb/diploid genome (replicates=3). Expression of telomerase components TERT and TERC, DKC was compared to the mRNA level by qRT-PCR in the TERC-mutant iPSCs. We found significant variation in mRNA expression levels of telomerase components the different lines of telomerase deficient iPSCs, and even variation among different clones of the same telomerase deficient line. We have also found that mutations in TERC results in defective hematopoietic differentiation from these iPSCs in in vitro assays. In the TERC-mutant iPSCs, the proportion of CD34+CD45+ hematopoietic cells was reduced compared to wild type controls. Wild type iPSCs produce 30% CD34+ cells compared to 15-20% in TERC-mutant iPSCs (n=3). Additionally, wild type iPSC controls produce 9-10% CD34+CD45+ hematopoietic progenitor cells compared to 1-2% of TERC mutant cells. Interestingly, approximately equal proportions (8-9%) of wild type and TERC-mutant cells differentiate into CD34+CD31+ endothelial cells, suggesting this pathway is less affected by the TERC mutation. The TERC-mutant iPSCs demonstrate reduced development of hematopoietic progenitor cells in standard hematopoietic colony forming cell assays: 100 CFCs per 50,000 differentiated wild type iPSC-derived cells compared to 65 CFCs per 50,000 differentiated TERC mutant iPSC-derived cells. In order to rescue the hematopoietic defect in telomerase deficient TERC-mutant iPSCs we have used the Sleeping Beauty transposon system to over express these telomerase components TERC and TERT in the TERC mutant iPSCs. We are currently characterizing the effect of overexpression of these telomerase components on hematopoietic differentiation to determine if this provides a strategy to enable use of gene-corrected iPSCs to provide a future therapy for patients with bone marrow failure due to defined telomerase deficiencies. Disclosures No relevant conflicts of interest to declare.
24
Longtine, M. S., S. Enomoto, S. L. Finstad, and J. Berman. "Telomere-mediated plasmid segregation in Saccharomyces cerevisiae involves gene products required for transcriptional repression at silencers and telomeres." Genetics 133, no. 2 (February 1, 1993): 171–82. http://dx.doi.org/10.1093/genetics/133.2.171.
Анотація:
Abstract Plasmids that contain Saccharomyces cerevisiae TG1-3 telomere repeat sequences (TRS plasmids) segregate efficiently during mitosis. Mutations in histone H4 reduce the efficiency of TRS-mediated plasmid segregation, suggesting that chromatin structure is involved in this process. Sir2, Sir3 and Sir4 are required for the transcriptional repression of genes located at the silent mating type loci (HML and HMR) and at telomeres (telomere position effect) and are also involved in the segregation of TRS plasmids, indicating that TRS-mediated plasmid segregation involves factors that act at chromosomal telomeres. TRS plasmid segregation differes from the segregation of plasmids carrying the HMR E silencing region: HMR E plasmid segregation function is completely dependent upon Sir2, Sir3 and Sir4, involves Sir1 and is not influenced by mutations in RAP 1 that eliminate TRS plasmid segregation. Mutations in SIR1, SIN1, TOP1, TEL1 and TEL2 do not influence TRS plasmid segregation. Unlike transcriptional repression at telomeres, TRS plasmids retain partial segregation function in sir2, sir3, sir4, nat1 and ard1 mutant strains. Thus it is likely that TRS plasmid segregation involves additional factors that are not involved in telomere position effect.
25
Lee, Kyung-Ha, Do-Yeon Kim, and Wanil Kim. "Regulation of Gene Expression by Telomere Position Effect." International Journal of Molecular Sciences 22, no. 23 (November 26, 2021): 12807. http://dx.doi.org/10.3390/ijms222312807.
Анотація:
Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.
26
Iida, Tetsushi, та Hiroyuki Araki. "Noncompetitive Counteractions of DNA Polymerase ε and ISW2/yCHRAC for Epigenetic Inheritance of Telomere Position Effect in Saccharomyces cerevisiae". Molecular and Cellular Biology 24, № 1 (1 січня 2004): 217–27. http://dx.doi.org/10.1128/mcb.24.1.217-227.2004.
Анотація:
ABSTRACT Relocation of euchromatic genes near the heterochromatin region often results in mosaic gene silencing. In Saccharomyces cerevisiae, cells with the genes inserted at telomeric heterochromatin-like regions show a phenotypic variegation known as the telomere-position effect, and the epigenetic states are stably passed on to following generations. Here we show that the epigenetic states of the telomere gene are not stably inherited in cells either bearing a mutation in a catalytic subunit (Pol2) of replicative DNA polymerase ε (Pol ε) or lacking one of the nonessential and histone fold motif-containing subunits of Pol ε, Dpb3 and Dpb4. We also report a novel and putative chromatin-remodeling complex, ISW2/yCHRAC, that contains Isw2, Itc1, Dpb3-like subunit (Dls1), and Dpb4. Using the single-cell method developed in this study, we demonstrate that without Pol ε and ISW2/yCHRAC, the epigenetic states of the telomere are frequently switched. Furthermore, we reveal that Pol ε and ISW2/yCHRAC function independently: Pol ε operates for the stable inheritance of a silent state, while ISW2/yCHRAC works for that of an expressed state. We therefore propose that inheritance of specific epigenetic states of a telomere requires at least two counteracting regulators.
27
Mitra, Jaba, and Taekjip Ha. "Streamlining effects of extra telomeric repeat on telomeric DNA folding revealed by fluorescence-force spectroscopy." Nucleic Acids Research 47, no. 21 (October 16, 2019): 11044–56. http://dx.doi.org/10.1093/nar/gkz906.
Анотація:
Abstract A human telomere ends in a single-stranded 3′ tail, composed of repeats of T2AG3. G-quadruplexes (GQs) formed from four consecutive repeats have been shown to possess high-structural and mechanical diversity. In principle, a GQ can form from any four repeats that are not necessarily consecutive. To understand the dynamics of GQs with positional multiplicity, we studied five and six repeats human telomeric sequence using a combination of single molecule FRET and optical tweezers. Our results suggest preferential formation of GQs at the 3′ end both in K+ and Na+ solutions, with minor populations of 5′-GQ or long-loop GQs. A vectorial folding assay which mimics the directional nature of telomere extension showed that the 3′ preference holds even when folding is allowed to begin from the 5′ side. In 100 mM K+, the unassociated T2AG3 segment has a streamlining effect in that one or two mechanically distinct species was observed at a single position instead of six or more observed without an unassociated repeat. We did not observe such streamlining effect in 100 mM Na+. Location of GQ and reduction in conformational diversity in the presence of extra repeats have implications in telomerase inhibition, T-loop formation and telomere end protection.
28
Sandell, L. L., D. E. Gottschling, and V. A. Zakian. "Transcription of a yeast telomere alleviates telomere position effect without affecting chromosome stability." Proceedings of the National Academy of Sciences 91, no. 25 (December 6, 1994): 12061–65. http://dx.doi.org/10.1073/pnas.91.25.12061.
29
Prescott, John C., and Elizabeth H. Blackburn. "Telomerase RNA Template Mutations Reveal Sequence-Specific Requirements for the Activation and Repression of Telomerase Action at Telomeres." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2941–48. http://dx.doi.org/10.1128/mcb.20.8.2941-2948.2000.
Анотація:
ABSTRACT Telomeric DNA is maintained within a length range characteristic of an organism or cell type. Significant deviations outside this range are associated with altered telomere function. The yeast telomere-binding protein Rap1p negatively regulates telomere length. Telomere elongation is responsive to both the number of Rap1p molecules bound to a telomere and the Rap1p-centered DNA-protein complex at the extreme telomeric end. Previously, we showed that a specific trinucleotide substitution in the Saccharomyces cerevisiae telomerase gene (TLC1) RNA template abolished the enzymatic activity of telomerase, causing the same cell senescence and telomere shortening phenotypes as a complete tlc1 deletion. Here we analyze effects of six single- and double-base changes within these same three positions. All six mutant telomerases had in vitro enzymatic activity levels similar to the wild-type levels. The base changes predicted from the mutations all disrupted Rap1p binding in vitro to the corresponding duplex DNAs. However, they caused two classes of effects on telomere homeostasis: (i) rapid, RAD52-independent telomere lengthening and poor length regulation, whose severity correlated with the decrease in in vitro Rap1p binding affinity (this is consistent with loss of negative regulation of telomerase action at these telomeres; and (ii) telomere shortening that, depending on the template mutation, either established a new short telomere set length with normal cell growth or was progressive and led to cellular senescence. Hence, disrupting Rap1p binding at the telomeric terminus is not sufficient to deregulate telomere elongation. This provides further evidence that both positive and negativecis-acting regulators of telomerase act at telomeres.
30
Wyatt, Holly R., Hungjiun Liaw, George R. Green, and Arthur J. Lustig. "Multiple Roles for Saccharomyces cerevisiae Histone H2A in Telomere Position Effect, Spt Phenotypes and Double-Strand-Break Repair." Genetics 164, no. 1 (May 1, 2003): 47–64. http://dx.doi.org/10.1093/genetics/164.1.47.
Анотація:
Abstract Telomere position effects on transcription (TPE, or telomeric silencing) are nucleated by association of nonhistone silencing factors with the telomere and propagated in subtelomeric regions through association of silencing factors with the specifically modified histones H3 and H4. However, the function of histone H2A in TPE is unknown. We found that deletion of either the amino or the carboxyltails of H2A substantially reduces TPE. We identified four H2A modification sites necessary for wild-type efficiency of TPE. These “hta1tpe” alleles also act as suppressors of a δ insertion allele of LYS2, suggesting shared elements of chromatin structure at both loci. Interestingly, we observed combinatorial effects of allele pairs, suggesting both interdependent acetylation and deacetylation events in the amino-terminal tail and a regulatory circuit between multiple phosphorylated residues in the carboxyl-terminal tail. Decreases in silencing and viability are observed in most hta1tpe alleles after treatment with low and high concentrations, respectively, of bleomycin, which forms double-strand breaks (DSBs). In the absence of the DSB and telomere-binding protein yKu70, the bleomycin sensitivity of hta1tpe alleles is further enhanced. We also provide data suggesting the presence of a yKu-dependent histone H2A function in TPE. These data indicate that the amino- and carboxyl-terminal tails of H2A are essential for wild-type levels of yKu-mediated TPE and DSB repair.
31
Laberthonnière, Camille, Frédérique Magdinier, and Jérôme D. Robin. "Bring It to an End: Does Telomeres Size Matter?" Cells 8, no. 1 (January 8, 2019): 30. http://dx.doi.org/10.3390/cells8010030.
Анотація:
Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell proliferation crisis or senescence. Beyond this mitotic clock role attributed to the need for telomere to be maintained over a critical length, the very tip of our DNA has been shown to impact transcription by position effect. TPE and a long-reach counterpart, TPE-OLD, are mechanisms recently described in human biology. Still in infancy, the mechanism of action of these processes and their respective genome wide impact remain to be resolved. In this review, we will discuss recent findings on telomere dynamics, TPE, TPE-OLD, and lessons learnt from model organisms.
32
Robin, Jérôme D., Andrew T. Ludlow, Kimberly Batten, Frédérique Magdinier, Guido Stadler, Kathyrin R. Wagner, Jerry W. Shay, and Woodring E. Wright. "Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances." Genes & Development 28, no. 22 (November 15, 2014): 2464–76. http://dx.doi.org/10.1101/gad.251041.114.
33
Kim, Wanil, and Jerry W. Shay. "Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD)." Differentiation 99 (January 2018): 1–9. http://dx.doi.org/10.1016/j.diff.2017.11.005.
34
Stadler, Guido, Fedik Rahimov, Oliver D. King, Jennifer C. J. Chen, Jerome D. Robin, Kathryn R. Wagner, Jerry W. Shay, Charles P. Emerson, and Woodring E. Wright. "Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy." Nature Structural & Molecular Biology 20, no. 6 (May 5, 2013): 671–78. http://dx.doi.org/10.1038/nsmb.2571.
35
Sheng, H., Z. Hou, T. Schierer, D. L. Dobbs, and E. Henderson. "Identification and characterization of a putative telomere end-binding protein from Tetrahymena thermophila." Molecular and Cellular Biology 15, no. 3 (March 1995): 1144–53. http://dx.doi.org/10.1128/mcb.15.3.1144.
Анотація:
Telomeric DNA of Tetrahymena thermophila consists of a long stretch of (TTGGGG)n double-stranded repeats with a single-stranded (TTGGGG)2 3' overhang at the end of the chromosome. We have identified and characterized a protein that specifically binds to a synthetic telomeric substrate consisting of duplex DNA and the 3' telomeric repeat overhang. This protein is called TEP (telomere end-binding protein). A change from G to A in the third position of the TTGGGG overhang repeat converts the substrate to a human telomere analog and reduces the binding affinity approximately threefold. Changing two G's to C's in the TTGGGG repeats totally abolishes binding. However, permutation of the Tetrahymena repeat sequence has only a minor effect on binding. A duplex structure adjacent to the 3' overhang is required for binding, although the duplex need not contain telomeric repeats. TEP does not bind to G-quartet DNA, which is formed by many G-rich sequences. TEP has a greatly reduced affinity for RNA substrates. The copy number of TEP is at least 2 x 10(4) per cell, and it is present under different conditions of cell growth and development, although its level varies. UV cross-linking experiments show that TEP has an apparent molecular mass of approximately 65 kDa. Unlike other telomere end-binding proteins, TEP is sensitive to high salt concentrations.
36
Rehman, Muhammad Attiq, Dongliang Wang, Genevieve Fourel, Eric Gilson, and Krassimir Yankulov. "Subtelomeric ACS-containing Proto-silencers Act as Antisilencers in Replication Factors Mutants in Saccharomyces cerevisiae." Molecular Biology of the Cell 20, no. 2 (January 15, 2009): 631–41. http://dx.doi.org/10.1091/mbc.e08-01-0099.
Анотація:
Subtelomeric genes are either fully active or completely repressed and can switch their state about once per 20 generations. This meta-stable telomeric position effect is mediated by strong repression signals emitted by the telomere and relayed/enhanced by weaker repressor elements called proto-silencers. In addition, subtelomeric regions contain sequences with chromatin partitioning and antisilencing activities referred to as subtelomeric antisilencing regions. Using extensive mutational analysis of subtelomeric elements, we show that ARS consensus sequence (ACS)-containing proto-silencers convert to antisilencers in several replication factor mutants. We point out the significance of the B1 auxiliary sequence next to ACS in mediating these effects. In contrast, an origin-derived ACS does not convert to antisilencer in mutants and its B1 element has little bearing on silencing. These results are specific for the analyzed ACS and in addition to the effects of each mutation (relative to wild type) on global silencing. Another line of experiments shows that Mcm5p possesses antisilencing activity and is recruited to telomeres in an ACS-dependent manner. Mcm5p persists at this location at the late stages of S phase. We propose that telomeric ACS are not static proto-silencers but conduct finely tuned silencing and antisilencing activities mediated by ACS-bound factors.
37
Wang, Zhi-Ru, Leilei Guo, Lizhen Chen, and Michael J. McEachern. "Evidence for an Additional Base-Pairing Element between the Telomeric Repeat and the Telomerase RNA Template in Kluyveromyces lactis and Other Yeasts." Molecular and Cellular Biology 29, no. 20 (August 17, 2009): 5389–98. http://dx.doi.org/10.1128/mcb.00528-09.
Анотація:
ABSTRACT In all telomerases, the template region of the RNA subunit contains a region of telomere homology that is longer than the unit telomeric repeat. This allows a newly synthesized telomeric repeat to translocate back to the 3′ end of the template prior to a second round of telomeric repeat synthesis. In the yeast Kluyveromyces lactis, the telomerase RNA (Ter1) template has 30 nucleotides of perfect homology to the 25-bp telomeric repeat. Here we provide strong evidence that three additional nucleotides at positions −2 through −4 present on the 3′ side of the template form base-pairing interactions with telomeric DNA. Mutation of these bases can lead to opposite effects on telomere length depending on the sequence permutation of the template in a manner consistent with whether the mutation increases or decreases the base-pairing potential with the telomere. Additionally, mutations in the −2 and −3 positions that restore base-pairing potential can suppress corresponding sequence changes in the telomeric repeat. Finally, multiple other yeast species were found to also have telomerase RNAs that encode relatively long 7- to 10-nucleotide domains predicted to base pair, often with imperfect pairing, with telomeric DNA. We further demonstrate that K. lactis telomeric fragments produce banded patterns with a 25-bp periodicity. This indicates that K. lactis telomeres have preferred termination points within the 25-bp telomeric repeat.
38
Donaldson, Kathryn M., Amy Lui, and Gary H. Karpen. "Modifiers of Terminal Deficiency-Associated Position Effect Variegation in Drosophila." Genetics 160, no. 3 (March 1, 2002): 995–1009. http://dx.doi.org/10.1093/genetics/160.3.995.
Анотація:
Abstract Terminal deletions of a Drosophila minichromosome (Dp(1;f)1187) dramatically increase the position effect variegation (PEV) of a yellow+ body-color gene located in cis. Such terminal deficiency-associated PEV (TDA-PEV) can be suppressed by the presence of a second minichromosome, a phenomenon termed “trans-suppression.” We performed a screen for mutations that modify TDA-PEV and trans-suppression. Seventy suppressors and enhancers of TDA-PEV were identified, but no modifiers of trans-suppression were recovered. Secondary analyses of the effects of these mutations on different PEV types identified 10 mutations that modify only TDA-PEV and 6 mutations that modify TDA-PEV and only one other type of PEV. One mutation, a new allele of Su(var)3-9, affects all forms of PEV, including silencing associated with the insertion of a transgene into telomeric regions (TPE). This Su(var)3-9 allele is the first modifier of PEV to affect TPE and provides a unique link between different types of gene silencing in Drosophila. The remaining mutations affected multiple PEV types, indicating that general PEV modifiers impact TDA-PEV. Modifiers of TDA-PEV may identify proteins that play important roles in general heterochromatin biology, including proteins involved in telomere structure and function and the organization of chromosomes in the interphase nucleus.
39
Mohannath, Gireesha, Frederic Pontvianne, and Craig S. Pikaard. "Selective nucleolus organizer inactivation in Arabidopsis is a chromosome position-effect phenomenon." Proceedings of the National Academy of Sciences 113, no. 47 (November 7, 2016): 13426–31. http://dx.doi.org/10.1073/pnas.1608140113.
Анотація:
Nucleolus organizer regions (NORs) are chromosomal loci where hundreds of rRNA genes are clustered. Despite being nearly identical in sequence, specific rRNA genes are selected for silencing during development via choice mechanism(s) that remain unclear. In Arabidopsis thaliana, rRNA gene subtypes that are silenced during development were recently mapped to the NOR on chromosome 2, NOR2, whereas active rRNA genes map to NOR4, on chromosome 4. In a mutant line deficient for ATXR5 or ATXR6-dependent histone H3 lysine 27 (H3K27) monomethylation, we show that millions of base pairs of chromosome 4, including the telomere, TEL4N, and much of NOR4, have been converted to the corresponding sequences of chromosome 2. This genomic change places rRNA genes of NOR2, which are normally silenced, at the position on chromosome 4 where active rRNA genes are normally located. At their new location, NOR2-derived rRNA genes escape silencing, independent of the atxr mutations, indicating that selective rRNA gene silencing is chromosome 2-specific. The chromosome 2 position effect is not explained by the NOR2-associated telomere, TEL2N, which remains linked to the translocated NOR, implicating centromere-proximal sequences in silencing.
40
Jedrusik, Monika A., and Ekkehard Schulze. "Telomeric Position Effect Variegation in Saccharomyces cerevisiae by Caenorhabditis elegans Linker Histones Suggests a Mechanistic Connection between Germ Line and Telomeric Silencing." Molecular and Cellular Biology 23, no. 10 (May 15, 2003): 3681–91. http://dx.doi.org/10.1128/mcb.23.10.3681-3691.2003.
Анотація:
ABSTRACT Linker histones are nonessential for the life of single-celled eukaryotes. Linker histones, however, can be important components of specific developmental programs in multicellular animals and plants. For Caenorhabditis elegans a single linker histone variant (H1.1) is essential in a chromatin silencing process which is crucial for the proliferation and differentiation of the hermaphrodite germ line. In this study we analyzed the whole linker histone complement of C. elegans by telomeric position effect variegation in budding yeast. In this assay an indicator gene (URA3) placed close to the repressive telomeric chromatin structure is subject to epigenetically inherited gene inactivation. Just one out of seven C. elegans linker histones (H1.1) was able to enhance the telomeric position effect in budding yeast. Since these results reflect the biological function of H1.1 in C. elegans, we suggest that chromatin silencing in C. elegans is governed by molecular mechanisms related to the telomere-dependent silencing in budding yeast. We confirmed this hypothesis by testing C. elegans homologs of three yeast genes which are established modifiers of the yeast telomeric chromatin structure (SIR2, SET1, and RAD17) for their influence on repeat-dependent transgene silencing for C. elegans.
41
Palmer, Jonathan M., Sandeep Mallaredy, Dustin W. Perry, James F. Sanchez, Jeffrey M. Theisen, Edyta Szewczyk, Berl R. Oakley, Clay C. C. Wang, Nancy P. Keller, and Peter M. Mirabito. "Telomere position effect is regulated by heterochromatin-associated proteins and NkuA in Aspergillus nidulans." Microbiology 156, no. 12 (December 1, 2010): 3522–31. http://dx.doi.org/10.1099/mic.0.039255-0.
Анотація:
Gene-silencing mechanisms are being shown to be associated with an increasing number of fungal developmental processes. Telomere position effect (TPE) is a eukaryotic phenomenon resulting in gene repression in areas immediately adjacent to telomere caps. Here, TPE is shown to regulate expression of transgenes on the left arm of chromosome III and the right arm of chromosome VI in Aspergillus nidulans. Phenotypes found to be associated with transgene repression included reduction in radial growth and the absence of sexual spores; however, these pleiotropic phenotypes were remedied when cultures were grown on media with appropriate supplementation. Simple radial growth and ascosporogenesis assays provided insights into the mechanism of TPE, including a means to determine its extent. These experiments revealed that the KU70 homologue (NkuA) and the heterochromatin-associated proteins HepA, ClrD and HdaA were partially required for transgene silencing. This study indicates that TPE extends at least 30 kb on chromosome III, suggesting that this phenomenon may be important for gene regulation in subtelomeric regions of A. nidulans.
42
Weuts, An, Thierry Voet, Jelle Verbeeck, Nathalie Lambrechts, Evelyne Wirix, Luc Schoonjans, Sophie Danloy, Peter Marynen, and Guy Froyen. "Telomere length homeostasis and telomere position effect on a linear human artificial chromosome are dictated by the genetic background." Nucleic Acids Research 40, no. 22 (October 11, 2012): 11477–89. http://dx.doi.org/10.1093/nar/gks926.
43
Yegorov, Y. E. "Olovnikov, telomeres and telomerase. is it possible to prolong a healthy life?" Биохимия 88, no. 11 (December 15, 2023): 2066–83. http://dx.doi.org/10.31857/s0320972523110040.
Анотація:
The science of telomeres and telomerase has made tremendous progress in recent decades. In this review, we consider it first in a historical context (the Carrel-Hayflick-Olovnikov-Blackburn chain of discoveries) and then review current knowledge of telomere structure and dynamics in norm and pathology. Central to the review are the consequences of telomere shortening, including telomere position effects, DNA damage signaling, and increased genetic instability. Cell senescence and the role of telomere length in its development are discussed separately. Therapeutic aspects and risks of telomerase and other telomere lengthening methods are also discussed.
44
Yegorov, Yegor E. "Olovnikov, Telomeres, and Telomerase. Is It Possible to Prolong a Healthy Life?" Biochemistry (Moscow) 88, no. 11 (November 2023): 1704–18. http://dx.doi.org/10.1134/s0006297923110032.
Анотація:
Abstract The science of telomeres and telomerase has made tremendous progress in recent decades. In this review, we consider it first in a historical context (the Carrel–Hayflick–Olovnikov–Blackburn chain of discoveries) and then review current knowledge on the telomere structure and dynamics in norm and pathology. Central to the review are consequences of the telomere shortening, including telomere position effects, DNA damage signaling, and increased genetic instability. Cell senescence and role of telomere length in its development are discussed separately. Therapeutic aspects and risks of telomere lengthening methods including use of telomerase and other approaches are also discussed.
45
Brümmendorf, Tim H., Nora Pällmann, Michael Preukschas, Doris Steinemann, Winfried Hofmann, Anne Gompf, Karl L. Rudolph, et al. "BCR-ABL Cooperates With a “Telomere-Associated Secretory Phenotype” (TASP) To Facilitate Malignant Proliferation Of Hematopoietic Stem Cells." Blood 122, no. 21 (November 15, 2013): 3976. http://dx.doi.org/10.1182/blood.v122.21.3976.3976.
Анотація:
Abstract Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC) disease caused by the reciprocal translocation t(9;22). Although there is clear evidence that the resulting oncogenic tyrosine kinase BCR-ABL is the key event of leukemia initiation which drives stem cell proliferation and expansion of myeloid progenitors in early chronic phase (CP), the mechanism leading to advanced phases remains elusive. Recently, we could show that telomere attrition correlates with disease stages due to increased leukemic stem cell turnover. Here, we could provide first time evidence that this can functionally contribute to disease progression in CML. In our study we made use of the well-described telomerase knockout mouse model (mTR-/-), lacking the RNA subunit of telomerase and resulting in significant telomere shortening with each generation, and retrovirally introduced BCR-ABL into primary bone marrow cells of different generation. Although all CML-like cultures (hereafter referred to as “CML”) grew exponentially and growth factor independently in vitro, they showed remarkable differences in cellular growth kinetics depending on the generation of mTR-/-mice the cells were derived from. CML-HSCs of generation iG4 (CML-iG4) are functionally impaired with respect to their growth properties and ceased to proliferate due to a robust senescent-like cell cycle arrest. Interestingly, they did not show overt genomic instability, but and are less susceptible to Imatinib-induced apoptosis compared to wildtype cells (CML-WT). In sharp contrast, CML-G2 cells with only pre-shortened telomere lengths grew most rapidly and presented with an impressive proliferation advantage compared to CML-WT and -iG4 cells, while they still retain Imatinib sensitivity. Notably, we uncovered that this growth advantage is related to a “telomere-associated secretory phenotype” (TASP), comprising the upregulation and secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth in an autocrine fashion. In line with those observations, we found that conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 HSCs. To investigate if a TPE (telomere position effect)-related mechanism is responsible for inducing inflammatory gene expression in BCR-ABL positive cells, we mapped selected TASP genes for their chromosomal location. However, although they are frequently found in well-known cluster (e.g. chemokines), TASP genes are not preferentially located close to the (sub-) telomere. This suggests that a yet unknown mechanism controls TASP gene expression upon telomere shortening. Most importantly, a similar inflammatory mRNA expression pattern was found in CML patients of accelerated phase (AP), but not in blast crisis (BC). Taken together, those data support the hypothesis that accelerated telomere shortening contributes to disease progression in BCR-ABL-driven leukemogenesis by the expression of an inflammatory signature, while telomere-induced senescence needs to be bypassed (e.g. by upregulation of telomerase) in order for leukemic cells to be able to progress to blast crisis (BC) CML. Disclosures: Brümmendorf: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Ariad: Consultancy.
46
Balasov, M. L. "Genetic factors controlling white gene expression of the transposon AR4-24 at a telomere in Drosophila melanogaster." Genome 45, no. 6 (December 1, 2002): 1025–34. http://dx.doi.org/10.1139/g02-074.
Анотація:
The position effect of the AR 4-24 P[white, rosy] transposon was studied at cytological position 60F. Three copies of the transposon (within ~50-kb region) resulted in a spatially restricted pattern of white variegation. This pattern was modified by temperature and by removal of the Y chromosome, suggesting that it was due to classical heterochromatin-induced position effect variegation (PEV). In contrast with classical PEV, extra dose of the heterochromatin protein 1 (HP1) suppressed white variegation and one dose enhanced it. The effect of Pc-G, trx-G, and other PEV suppressors was also tested. It was found that E(Pc)1, TrlR85, and mutations of Su(z)2C relieve AR 4-24- silencing and z1 enhances it. To explain the results obtained with these modifiers, it is proposed that PEV and telomeric position effect can counteract each other at this particular cytological site.Key words: position effect variegation, heterochromatin protein 1, Drosophila melanogaster.
47
Robin, Jérôme D., Andrew T. Ludlow, Kimberly Batten, Marie-Cécile Gaillard, Guido Stadler, Frédérique Magdinier, Woodring E. Wright, and Jerry W. Shay. "SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy." Genome Research 25, no. 12 (September 10, 2015): 1781–90. http://dx.doi.org/10.1101/gr.190660.115.
48
Babbs, Christian, Jill Brown, Sharon W. Horsley, Joanne Slater, Evie Maifoshie, Shiwangini Kumar, Paul Ooijevaar, et al. "ATR-16 syndrome: mechanisms linking monosomy to phenotype." Journal of Medical Genetics 57, no. 6 (January 31, 2020): 414–21. http://dx.doi.org/10.1136/jmedgenet-2019-106528.
Анотація:
BackgroundDeletions removing 100s–1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.MethodsHere, as an example of this common phenomenon, we analysed 41 patients with simple deletions of ~177 to ~2000 kb affecting one allele of the well-characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised deletion extents and screened for genetic background effects, telomere position effect and compensatory upregulation of hemizygous genes.ResultsWe find the risk of developmental and neurological abnormalities arises from much smaller distal chromosome 16 deletions (~400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes; however, genetic background effects substantially modify phenotypic abnormalities.ConclusionsUsing ATR-16 as a general model of disorders caused by CNVs, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.
49
Smith, Jeffrey S., Emerita Caputo, and Jef D. Boeke. "A Genetic Screen for Ribosomal DNA Silencing Defects Identifies Multiple DNA Replication and Chromatin-Modulating Factors." Molecular and Cellular Biology 19, no. 4 (April 1, 1999): 3184–97. http://dx.doi.org/10.1128/mcb.19.4.3184.
Анотація:
ABSTRACT Transcriptional silencing in Saccharomyces cerevisiaeoccurs at several genetic loci, including the ribosomal DNA (rDNA). Silencing at telomeres (telomere position effect [TPE]) and the cryptic mating-type loci (HML and HMR) depends on the silent information regulator genes, SIR1,SIR2, SIR3, and SIR4. However, silencing of polymerase II-transcribed reporter genes integrated within the rDNA locus (rDNA silencing) requires only SIR2. The mechanism of rDNA silencing is therefore distinct from TPE andHM silencing. Few genes other than SIR2 have so far been linked to the rDNA silencing process. To identify additional non-Sir factors that affect rDNA silencing, we performed a genetic screen designed to isolate mutations which alter the expression of reporter genes integrated within the rDNA. We isolated two classes of mutants: those with a loss of rDNA silencing (lrs) phenotype and those with an increased rDNA silencing (irs) phenotype. Using transposon mutagenesis,lrs mutants were found in 11 different genes, andirs mutants were found in 22 different genes. Surprisingly, we did not isolate any genes involved in rRNA transcription. Instead, multiple genes associated with DNA replication and modulation of chromatin structure were isolated. We describe these two gene classes, and two previously uncharacterized genes, LRS4 andIRS4. Further characterization of the lrs andirs mutants revealed that many had alterations in rDNA chromatin structure. Several lrs mutants, including those in the cdc17 and rfc1 genes, caused lengthened telomeres, consistent with the hypothesis that telomere length modulates rDNA silencing. Mutations in the HDB (RPD3) histone deacetylase complex paradoxically increased rDNA silencing by aSIR2-dependent, SIR3-independent mechanism. Mutations in rpd3 also restored mating competence selectively to sir3Δ MATα strains, suggesting restoration of silencing at HMR in a sir3mutant background.
50
Dehé, Pierre-Marie, and Vincent Géli. "The multiple faces of Set1This paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 84, no. 4 (August 2006): 536–48. http://dx.doi.org/10.1139/o06-081.
Анотація:
In Saccharomyces cerevisiae, H3 methylation at lysine 4 (H3K4) is mediated by Set1. Set1 is a large protein bearing a conserved RNA recognition motif in addition to its catalytic C-terminal SET domain. The SET and RRM domains are conserved in Set1 orthologs from yeast to humans. Set1 belongs to a complex of 8 proteins, also showing a striking conservation, most subunits being required to efficiently catalyze methylation of H3K4. The deletion of SET1 is not lethal but has pleiotropic phenotypes. It affects growth, transcriptional activation, repression and elongation, telomere length regulation, telomeric position effect, rDNA silencing, meiotic differentiation, DNA repair, chromosome segregation, and cell wall organization. In this review, we discuss the regulation of H3K4 methylation and try to link Set1 activity with the multiple phenotypes displayed by cells lacking Set1. We also suggest that Set1 may have multiple targets.