Статті в журналах: "DNA Double-strand Break Repair (DSRB) Pathway"

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Wynn, Emily, Emma Purfeerst, and Alan Christensen. "Mitochondrial DNA Repair in an Arabidopsis thaliana Uracil N-Glycosylase Mutant." Plants 9, no. 2 (February 18, 2020): 261. http://dx.doi.org/10.3390/plants9020261.

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Substitution rates in plant mitochondrial genes are extremely low, indicating strong selective pressure as well as efficient repair. Plant mitochondria possess base excision repair pathways; however, many repair pathways such as nucleotide excision repair and mismatch repair appear to be absent. In the absence of these pathways, many DNA lesions must be repaired by a different mechanism. To test the hypothesis that double-strand break repair (DSBR) is that mechanism, we maintained independent self-crossing lineages of plants deficient in uracil-N-glycosylase (UNG) for 11 generations to determine the repair outcomes when that pathway is missing. Surprisingly, no single nucleotide polymorphisms (SNPs) were fixed in any line in generation 11. The pattern of heteroplasmic SNPs was also unaltered through 11 generations. When the rate of cytosine deamination was increased by mitochondrial expression of the cytosine deaminase APOBEC3G, there was an increase in heteroplasmic SNPs but only in mature leaves. Clearly, DNA maintenance in reproductive meristem mitochondria is very effective in the absence of UNG while mitochondrial genomes in differentiated tissue are maintained through a different mechanism or not at all. Several genes involved in DSBR are upregulated in the absence of UNG, indicating that double-strand break repair is a general system of repair in plant mitochondria. It is important to note that the developmental stage of tissues is critically important for these types of experiments.

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Zhao, Fei, Wootae Kim, Jake A. Kloeber, and Zhenkun Lou. "DNA end resection and its role in DNA replication and DSB repair choice in mammalian cells." Experimental & Molecular Medicine 52, no. 10 (October 2020): 1705–14. http://dx.doi.org/10.1038/s12276-020-00519-1.

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Abstract DNA end resection has a key role in double-strand break repair and DNA replication. Defective DNA end resection can cause malfunctions in DNA repair and replication, leading to greater genomic instability. DNA end resection is initiated by MRN-CtIP generating short, 3′-single-stranded DNA (ssDNA). This newly generated ssDNA is further elongated by multiple nucleases and DNA helicases, such as EXO1, DNA2, and BLM. Effective DNA end resection is essential for error-free homologous recombination DNA repair, the degradation of incorrectly replicated DNA and double-strand break repair choice. Because of its importance in DNA repair, DNA end resection is strictly regulated. Numerous mechanisms have been reported to regulate the initiation, extension, and termination of DNA end resection. Here, we review the general process of DNA end resection and its role in DNA replication and repair pathway choice.

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Blasiak, Janusz, Joanna Szczepańska, Anna Sobczuk, Michal Fila, and Elzbieta Pawlowska. "RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair." International Journal of Molecular Sciences 22, no. 21 (October 23, 2021): 11440. http://dx.doi.org/10.3390/ijms222111440.

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Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.

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Lee, Kyung-Jong, Janapriya Saha, Jingxin Sun, Kazi R. Fattah, Shu-Chi Wang, Burkhard Jakob, Linfeng Chi, et al. "Phosphorylation of Ku dictates DNA double-strand break (DSB) repair pathway choice in S phase." Nucleic Acids Research 44, no. 4 (December 27, 2015): 1732–45. http://dx.doi.org/10.1093/nar/gkv1499.

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Eskes, Robert, Lu Liu, Hongwen Ma, Michael Y. Chao, Lorna Dickson, Alan M. Lambowitz, and Philip S. Perlman. "Multiple Homing Pathways Used by Yeast Mitochondrial Group II Introns." Molecular and Cellular Biology 20, no. 22 (November 15, 2000): 8432–46. http://dx.doi.org/10.1128/mcb.20.22.8432-8446.2000.

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ABSTRACT The yeast mitochondrial DNA group II introns aI1 and aI2 are retroelements that insert site specifically into intronless alleles by a process called homing. Here, we used patterns of flanking marker coconversion in crosses with wild-type and mutant aI2 introns to distinguish three coexisting homing pathways: two that were reverse transcriptase (RT) dependent (retrohoming) and one that was RT independent. All three pathways are initiated by cleavage of the recipient DNA target site by the intron-encoded endonuclease, with the sense strand cleaved by partial or complete reverse splicing, and the antisense strand cleaved by the intron-encoded protein. The major retrohoming pathway in standard crosses leads to insertion of the intron with unidirectional coconversion of upstream exon sequences. This pattern of coconversion suggests that the major retrohoming pathway is initiated by target DNA-primed reverse transcription of the reverse-spliced intron RNA and completed by double-strand break repair (DSBR) recombination with the donor allele. The RT-independent pathway leads to insertion of the intron with bidirectional coconversion and presumably occurs by a conventional DSBR recombination mechanism initiated by cleavage of the recipient DNA target site by the intron-encoded endonuclease, as for group I intron homing. Finally, some mutant DNA target sites shift up to 43% of retrohoming to another pathway not previously detected for aI2 in which there is no coconversion of flanking exon sequences. This new pathway presumably involves synthesis of a full-length cDNA copy of the inserted intron RNA, with completion by a repair process independent of homologous recombination, as found for the Lactococcus lactis Ll.LtrB intron. Our results show that group II intron mobility can occur by multiple pathways, the ratios of which depend on the characteristics of both the intron and the DNA target site. This remarkable flexibility enables group II introns to use different recombination and repair enzymes in different host cells.

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Liu, X. X., C. Sun, X. D. Jin, P. Li, X. G. Zheng, T. Zhao, and Q. Li. "Genistein sensitizes sarcoma cells in vitro and in vivo by enhancing apoptosis and by inhibiting DSB repair pathways." Journal of Radiation Research 57, no. 3 (June 1, 2016): 227–37. http://dx.doi.org/10.1093/jrr/rrv091.

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Abstract The aim of this work was to investigate the radiosensitization effects of genistein on mice sarcoma cells and the corresponding biological mechanisms in vitro and in vivo . Using the non-toxic dosage of 10 μM genistein, the sensitizer enhancement ratios after exposure to X-rays at 50% cell survival (IC 50 ) was 1.45 for S180 cells. For mice cotreated with genistein and X-rays, the excised tumor tissues had reduced blood vessels and decreased size and volume compared with the control and irradiation-only groups. Moreover, a significant increase in apoptosis was accompanied by upregulation of Bax and downregulation of Bcl-2 in the mitochondria, and lots of cytochrome c being transferred to the cytoplasm. Furthermore, X-rays combined with genistein inhibited the activity of DNA-PKcs, so DNA-injured sites were dominated by Ku70/80, leading to incompleteness of homologous recombination (HR) and non-homologous end-joining (NHEJ) repairs and the eventual occurrence of cell apoptosis. Our study, for the first time, demonstrated that genistein sensitized sarcoma cells to X-rays and that this radiosensitizing effect depended on induction of the mitochondrial apoptosis pathway and inhibition of the double-strand break (DSB) repair pathways.

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7

White, Malcolm F. "Homologous recombination in the archaea: the means justify the ends." Biochemical Society Transactions 39, no. 1 (January 19, 2011): 15–19. http://dx.doi.org/10.1042/bst0390015.

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The process of information exchange between two homologous DNA duplexes is known as homologous recombination (HR) or double-strand break repair (DSBR), depending on the context. HR is the fundamental process underlying the genome shuffling that expands genetic diversity (for example during meiosis in eukaryotes). DSBR is an essential repair pathway in all three domains of life, and plays a major role in the rescue of stalled or collapsed replication forks, a phenomenon known as recombination-dependent replication (RDR). The process of HR in the archaea is gradually being elucidated, initially from structural and biochemical studies, but increasingly using new genetic systems. The present review focuses on our current understanding of the structures, functions and interactions of archaeal HR proteins, with an emphasis on recent advances. There are still many unknown aspects of archaeal HR, most notably the mechanism of branch migration of Holliday junctions, which is also an open question in eukarya.

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Krieger, Lisa Marie, Emil Mladenov, Aashish Soni, Marilen Demond, Martin Stuschke, and George Iliakis. "Disruption of Chromatin Dynamics by Hypotonic Stress Suppresses HR and Shifts DSB Processing to Error-Prone SSA." International Journal of Molecular Sciences 22, no. 20 (October 11, 2021): 10957. http://dx.doi.org/10.3390/ijms222010957.

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The processing of DNA double-strand breaks (DSBs) depends on the dynamic characteristics of chromatin. To investigate how abrupt changes in chromatin compaction alter these dynamics and affect DSB processing and repair, we exposed irradiated cells to hypotonic stress (HypoS). Densitometric and chromosome-length analyses show that HypoS transiently decompacts chromatin without inducing histone modifications known from regulated local chromatin decondensation, or changes in Micrococcal Nuclease (MNase) sensitivity. HypoS leaves undisturbed initial stages of DNA-damage-response (DDR), such as radiation-induced ATM activation and H2AX-phosphorylation. However, detection of ATM-pS1981, γ-H2AX and 53BP1 foci is reduced in a protein, cell cycle phase and cell line dependent manner; likely secondary to chromatin decompaction that disrupts the focal organization of DDR proteins. While HypoS only exerts small effects on classical nonhomologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ), it markedly suppresses homologous recombination (HR) without affecting DNA end-resection at DSBs, and clearly enhances single-strand annealing (SSA). These shifts in pathway engagement are accompanied by decreases in HR-dependent chromatid-break repair in the G2-phase, and by increases in alt-EJ and SSA-dependent chromosomal translocations. Consequently, HypoS sensitizes cells to ionizing radiation (IR)-induced killing. We conclude that HypoS-induced global chromatin decompaction compromises regulated chromatin dynamics and genomic stability by suppressing DSB-processing by HR, and allowing error-prone processing by alt-EJ and SSA.

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Langer, L. R., J. Papp, J. S. Sinsheimer, L. Kwan, J. Seldon, E. F. Reed, S. Dandekar, Y. Korin, Z. F. Zhang, and P. A. Ganz. "Breast cancer and DNA epair gene SNPs in a family cancer registry population." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10514. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10514.

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10514 Background: Alterations in the DNA double-strand break repair (DSBR) pathway are associated with cancer risk. Mutations in the genes BRCA1/2 disrupt DNA DSBR. Variations in breast cancer penetrance among BRCA1/2 mutation carriers, and familial patterns among women without known BRCA1/2 mutations may be related to polymorphisms of genes in the DNA-DSBR pathway. Methods: Using a case-control study design with individuals in the UCLA Family Cancer Registry (FCR), we examined the independent effects of 100 SNPs in 19 DNA-DSBR genes. SNPs were assayed using the Applied Biosystems SNPlex™ assay. Results: 630 consecutive females from 508 families in the UCLA FCR selected for familial risk of breast cancer were included in the study. Table 1 describes select subject characteristics. Preliminary association analysis of the Caucasian subset using a nonparametric permutation method, which controls for Ashkenazi Jewish heritage and dependencies among relatives, suggests that polymorphisms within RAD21 (p=0.0044, p=0.0005), XRCC2 (p = 0.0069), XRCC4 (p =0.0511), and BRIP1 (p =0.0107) may be associated with a change in risk of breast cancer. Using only unrelated Caucasian subjects in a logistic regression analysis with covariates such as age, BMI, and Ashkenazi Jewish heritage, the effects of these polymorphisms remain significant, with 32% to 74% change in the odds of breast cancer. Conclusions: We have identified five potential SNPs in genes in the DNA-DSBR pathway that appear to be associated with a change in risk of breast cancer. This hypothesis generating study lends support to a role for polymorphisms of the DNA-repair pathway in breast carcinogenesis. Assessment of gene-environment and gene-gene interactions will help to elucidate carcinogenic mechanisms. Further validation in similar populations is warranted. (Funded by the Breast Cancer Research Foundation and NIH/NCI CA87949 R25 Career Development Program.) [Table: see text] No significant financial relationships to disclose.

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Schötz, Ulrike, Viola Balzer, Friedrich-Wilhelm Brandt, Frank Ziemann, Florentine S. B. Subtil, Thorsten Rieckmann, Sabrina Köcher, et al. "Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining." Cancers 12, no. 2 (February 18, 2020): 467. http://dx.doi.org/10.3390/cancers12020467.

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The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status.

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Goodarzi, Aaron A., Angela T. Noon, and Penny A. Jeggo. "The impact of heterochromatin on DSB repair." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 569–76. http://dx.doi.org/10.1042/bst0370569.

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DNA NHEJ (non-homologous end-joining) is the major DNA DSB (double-strand break) repair pathway in mammalian cells. Although NHEJ-defective cell lines show marked DSB-repair defects, cells defective in ATM (ataxia telangiectasia mutated) repair most DSBs normally. Thus NHEJ functions independently of ATM signalling. However, ∼15% of radiation-induced DSBs are repaired with slow kinetics and require ATM and the nuclease Artemis. DSBs persisting in the presence of an ATM inhibitor, ATMi, localize to heterochromatin, suggesting that ATM is required for repairing DSBs arising within or close to heterochromatin. Consistent with this, we show that siRNA (small interfering RNA) of key heterochromatic proteins, including KAP-1 [KRAB (Krüppel-associated box) domain-associated protein 1], HP1 (heterochromatin protein 1) and HDAC (histone deacetylase) 1/2, relieves the requirement for ATM for DSB repair. Furthermore, ATMi addition to cell lines with genetic alterations that have an impact on heterochromatin, including Suv39H1/2 (suppressor of variegation 3–9 homologue 1/2)-knockout, ICFa (immunodeficiency, centromeric region instability, facial anomalies syndrome type a) and Hutchinson–Guilford progeria cell lines, fails to have an impact on DSB repair. KAP-1 is a highly dose-dependent, transient and ATM-specific substrate, and mutation of the ATM phosphorylation site on KAP-1 influences DSB repair. Collectively, the findings show that ATM functions to overcome the barrier to DSB repair posed by heterochromatin. However, even in the presence of ATM, γ-H2AX (phosphorylated histone H2AX) foci form on the periphery rather than within heterochromatic centres. Finally, we show that KAP-1's association with heterochromatin is diminished as cells progress through mitosis. We propose that KAP-1 is a critical heterochromatic factor that undergoes specific modifications to promote DSB repair and mitotic progression in a manner that allows localized and transient chromatin relaxation, but precludes significant dismantling of the heterochromatic superstructure.

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Lascarez-Lagunas, Laura I., Marina Martinez-Garcia, Saravanapriah Nadarajan, Brianna N. Diaz-Pacheco, Elizaveta Berson, and Mónica P. Colaiácovo. "Chromatin landscape, DSB levels, and cKU-70/80 contribute to patterning of meiotic DSB processing along chromosomes in C. elegans." PLOS Genetics 19, no. 1 (January 27, 2023): e1010627. http://dx.doi.org/10.1371/journal.pgen.1010627.

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Programmed DNA double-strand break (DSB) formation is essential for achieving accurate chromosome segregation during meiosis. DSB repair timing and template choice are tightly regulated. However, little is known about how DSB distribution and the choice of repair pathway are regulated along the length of chromosomes, which has direct effects on the recombination landscape and chromosome remodeling at late prophase I. Here, we use the spatiotemporal resolution of meiosis in the Caenorhabditis elegans germline along with genetic approaches to study distribution of DSB processing and its regulation. High-resolution imaging of computationally straightened chromosomes immunostained for the RAD-51 recombinase marking DSB repair sites reveals that the pattern of RAD-51 foci throughout pachytene resembles crossover distribution in wild type. Specifically, RAD-51 foci occur primarily along the gene-poor distal thirds of the chromosomes in both early and late pachytene, and on both the X and the autosomes. However, this biased off-center distribution can be abrogated by the formation of excess DSBs. Reduced condensin function, but not an increase in total physical axial length, results in a homogeneous distribution of RAD-51 foci, whereas regulation of H3K9 methylation is required for the enrichment of RAD-51 at off-center positions. Finally, the DSB recognition heterodimer cKU-70/80, but not the non-homologous end-joining canonical ligase LIG-4, contributes to the enriched off-center distribution of RAD-51 foci. Taken together, our data supports a model by which regulation of the chromatin landscape, DSB levels, and DSB detection by cKU-70/80 collaborate to promote DSB processing by homologous recombination at off-center regions of the chromosomes in C. elegans.

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O'Shaughnessy, Joyce, Virginia A. Espina, Irene Cherni, John D. Carpten, Lance A. Liotta, David W. Craig, Jeff Kiefer, et al. "Dual inhibition of DNA double strand break (DSB) repair and PI3K pathway with BEZ235 (BEZ) to sensitize refractory metastatic (met) triple negative breast cancer (TNBC) to nab paclitaxel/cisplatin (pac/cis) in a patient with an exceptional response (ExRx)." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 156. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.156.

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156 Background: Whether EGFR is a critical target in met TNBC is unknown. Here we report the clinical history & tumor molecular alterations in a patient with refractory metTNBC who had an ExRx to pac/cis. Methods: Following IRB-approved informed consent, targeted NGS (Foundation Medicine) and WGS (TGEN) was performed on the pt’s FFPE primary TNBC and 2 recurrent lymph nodes to characterize all classes of genomic alterations in cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theranostics Health) and George Mason Univ where immunostaining was directed against HER1/2/3 pathway and other proteins. Results: At age 58 in 2006, pt had T1c 1+ node TNBC treated with FAC/T. Between 2008 and 2011 she had 4 chemotherapy-refractory recurrences in axilla, supraclavicular (SC), internal mammary (IM) LNs treated unsuccessfully with surgery, radiation and multiple cytotoxic agents including carboplatin. In 2011, following SC LN biopsy, she was treated with BEZ, a PI3K/mTOR, ATM, ATR, DNA-PKcs inhibitor, had a 3 mo response, followed by rapidly enlarging progressive disease (PD) in IM LNs pushing sternum anteriorly. She was treated with pac/cis and had an ongoing complete response (CR) of 2.5+ yrs. NGS of 2011 SC LN (pre-BEZ) & 2012 IM LN (post-BEZ): TP53 & BRCA2 (somatic 15% mutant allele freq) mutations, FOXM1 amplification; SMARCA4 (BRG1) deletion RPPA (GMU) 2011 SC LN (Pre-BEZ): 3+ EGFR; 2+ p-EGFR, p-AKT, p-MEK1/2, p-mTOR RPPA (Theranostics) 2012 IM LN (post-BEZ): 3+ p-MEK1/2 (EGFR & p-EGFR 0) (AR-). Conclusions: Strong EGFR signaling associated with chemo-resistant metTNBC in 2011 SC LN was not present in post-BEZ rapid PD in IM LN which then had durable CR with pac/cis. BEZ inhibits DSB repair, sensitizing cancers to DNA damaging agents (Gil del Alcazar, Clin Ca Res 20:1235, 2014). Progression of p-AKT-activated TNBC following response to inhibitors of PI3K & DNA repair shows DSB repair-deficiency and MAPK activation (Juvekar, Cancer Dis 2:1048, 2012). A prospective trial of BEZ followed at PD by pac/cis in metTNBC is warranted.

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Chatterjee, Nimrat, Christopher Lee Williams, Saleh Bhar, and Alison A. Bertuch. "A Novel Radiosensitivity Phenotype in Shwachman-Diamond Syndrome Is Mediated By ER Stress Response." Blood 126, no. 23 (December 3, 2015): 3618. http://dx.doi.org/10.1182/blood.v126.23.3618.3618.

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Abstract Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder, is characterized by bone marrow dysfunction, exocrine pancreatic insufficiency, congenital abnormalities, and leukemia predisposition (Myers et al., 2012). Most patients with SDS harbor biallelic mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS is known to play a role in ribosome biogenesis by enabling eviction of the ribosome anti-association factor eIF6 from the 60S ribosomal subunit, to allow formation of the 80S ribosome (Wong et al., 2011). SBDS-depleted cells are, therefore, defective in ribosome assembly. In addition, absence of SBDS sensitizes cells to ultraviolet irradiation, translation inhibitors, and endoplasmic reticulum (ER) stressors, such as tunicamycin (Ball et al., 2009). A recent report indicated that lymphoblastoid cell lines (LCLs) derived from two SDS patients accumulated more DNA damage after being exposed to ionizing radiation (IR) (Morini et al., 2015). A deficiency in DNA repair was alluded to as a possible cause, however, the mechanism underlying this previously unreported phenotype was not determined. In this study, we investigated LCLs derived from five SDS patients with biallelic SBDS mutations and found all to be hypersensitive to IR in a colony survival assay. In this assay, increasing doses of IR resulted in a significantly lower survival fraction in SDS-compared to control-LCLs. We found SBDS expression to increase in control-cells when stressed with IR, suggesting that SBDS is a stress response protein and its absence in SDS-LCLs induces hypersensitivity to IR. Because knockdown of SBDS in HEK293 cells induces an ER stress response (Ball et al., 2009), we examined the expression of the ER stress response factor phospho-eIF2α in untreated and IR exposed SDS-LCLs and found phospho-eIF2α expression to be markedly increased compared to controls. This result indicated that SDS-LCLs may have an activated ER stress response, as was further confirmed by exposing these cells to additional ER stressors, tunicamycin and H2O2, and observing a similar upregulation of phospho-eIF2α. Because ER stress is known to suppress DNA double strand break (DSBR) (Yamamori et al., 2013), we examined the expression of Rad51 and Ku70, which are required for the homology-directed and nonhomologous end-joining pathways of DSBR, respectively. Surprisingly, we found Rad51 and Ku70 protein levels to be repressed in SDS-LCLs compared to controls, both with and without exposure to IR. Collectively, these data support the hypothesis that, in addition to its role in ribosome biogenesis, SBDS is a stress response protein that plays an important role in regulating the ER stress response. In SDS-cells, where SBDS is lacking, activated ER stress represses DNA repair proteins rendering cells hypersensitive to IR and other stresses. This novel pathway to ER stress induction may contribute to the bone marrow failure and cancer predisposition seen in SDS patients. Disclosures No relevant conflicts of interest to declare.

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Vidaković, Melita, Goran Poznanović, and Juergen Bode. "DNA break repair: refined rules of an already complicated game." Biochemistry and Cell Biology 83, no. 3 (June 1, 2005): 365–73. http://dx.doi.org/10.1139/o05-044.

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Of the many types of DNA-damage repair, this review concentrates on the aspects of DNA single- and double-strand break repair. Originally considered to represent separate routes based on distinct enzymatic machineries, it has recently been shown that these pathways converge and are interlinked at a number of points. Poly(ADP-ribose) polymerase-1 (PARP-1) is a central player in this complicated game. We present new data and our view on the mechanisms by which PARP-1 is guided to its respective interaction partners to coordinate or participate in repair or apoptosis.Key words: DNA strand break repair (DSBR), non-homologous end joining (NHEJ), nuclear architecture, nuclear matrix, PARP-1.

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Zhao, Yucui, and Siyu Chen. "Targeting DNA Double-Strand Break (DSB) Repair to Counteract Tumor Radio-resistance." Current Drug Targets 20, no. 9 (June 11, 2019): 891–902. http://dx.doi.org/10.2174/1389450120666190222181857.

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During the last decade, advances of radiotherapy (RT) have been made in the clinical practice of cancer treatment. RT exerts its anticancer effect mainly via leading to the DNA Double-Strand Break (DSB), which is one of the most toxic DNA damages. Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) are two major DSB repair pathways in human cells. It is known that dysregulations of DSB repair elicit a predisposition to cancer and probably result in resistance to cancer therapies including RT. Therefore, targeting the DSB repair presents an attractive strategy to counteract radio-resistance. In this review, we describe the latest knowledge of the two DSB repair pathways, focusing on several key proteins contributing to the repair, such as DNA-PKcs, RAD51, MRN and PARP1. Most importantly, we discuss the possibility of overcoming radiation resistance by targeting these proteins for therapeutic inhibition. Recent tests of DSB repair inhibitors in the laboratory and their translations into clinical studies are also addressed.

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PORTIN, PETTER. "mus309 mutation, defective in DNA double-strand break repair, affects intergenic but not intragenic meiotic recombination in Drosophila melanogaster." Genetical Research 86, no. 3 (December 2005): 185–91. http://dx.doi.org/10.1017/s0016672305007883.

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The effect was investigated of the hypomorphic DNA double-strand break repair, notably synthesis-dependent strand annealing, deficient mutation mus309 on the third chromosome of Drosophila melanogaster on intergenic and intragenic meiotic recombination in the X chromosome. The results showed that the mutation significantly increases the frequency of intergenic crossing over in two of three gene intervals of the X chromosome studied. Interestingly the increase was most prevalent in the tip of the X chromosome where crossovers normally are least frequent per physical map unit length. In particular crossing over interference was also affected, indicating that the effect of the mus309 mutation involves preconditions of crossing over but not the event of crossing over itself. On the other hand, the results also show that most probably the mutation does not have any effect on intragenic recombination, i.e. gene conversion. These results are fully consistent with the present molecular models of meiotic crossing over initiated by double-strand breaks of DNA followed by formation of a single-end-invasion intermediate, or D-loop, which is subsequently processed to generate either crossover or non-crossover products involving formation of a double Holliday junction. In particular the results suggest that the mus309 gene is involved in resolution of the D-loop, thereby affecting the choice between double-strand-break repair (DSBR) and synthesis-dependent strand annealing (SDSA) pathways of meiotic recombination.

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Kollárovič, Gabriel, Caitríona E. Topping, Edward P. Shaw, and Anna L. Chambers. "The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination and contributes to DSB repair within heterochromatin." Nucleic Acids Research 48, no. 4 (December 5, 2019): 1872–85. http://dx.doi.org/10.1093/nar/gkz1146.

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Abstract Efficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes facilitate different DNA repair pathways, during different stages of the cell cycle and in varied chromatin environments. The contribution of remodelling factors to double-strand break repair within heterochromatin during G2 is unclear. The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We discover that HELLS facilitates homologous recombination at two-ended breaks and contributes to repair within heterochromatic regions during G2. HELLS promotes initiation of HR by facilitating end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.

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XU, DongYi, and HuaYu ZHAO. "Pathway choice for DNA double strand break repair." SCIENTIA SINICA Vitae 51, no. 1 (November 25, 2020): 56–69. http://dx.doi.org/10.1360/ssv-2020-0196.

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JOSEPH JERRY, D., NICHOLAS B. GRINER, and LUWEI TAO. "TUMOR SUPPRESSOR PATHWAYS AND CELLULAR ORIGINS OF BREAST CANCER: NEW COMPLEXITIES AND NEW HOPES." Nano LIFE 01, no. 01n02 (March 2010): 1–16. http://dx.doi.org/10.1142/s179398441000002x.

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Heritable breast cancer syndromes have identified the recognition and processing of DNA double strand breaks as a fundamental vulnerability in the breast epithelium. The role of homology-directed DNA repair is particularly prominent, indicating that this repair pathway is rate-limiting. Although the activities of the tumor suppressor genes underlying heritable breast cancer act in a common pathway of DNA double strand break repair, the specific lesions result in surprisingly different patterns of biomarkers in the breast cancers, suggesting that they arise from different cell types that include the luminal, basal and progenitor cells within the breast epithelium. Therefore, each cell type appears to have distinct underlying vulnerabilities in repair of DNA double strand breaks. While the heterogeneity of targets poses a challenge to develop specific therapies, these pathways also render tumor cells sensitive to drugs targeting double strand break repair pathways offering new options for therapies. As double strand break repair is a common pathway underlying breast cancer risk, therapies that enhance the proficiency of this pathway offer a strategy for chemoprevention.

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Dilworth, David, Fade Gong, Kyle Miller, and Christopher J. Nelson. "FKBP25 participates in DNA double-strand break repair." Biochemistry and Cell Biology 98, no. 1 (February 2020): 42–49. http://dx.doi.org/10.1139/bcb-2018-0328.

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FK506-binding proteins (FKBPs) alter the conformation of proteins via cis–trans isomerization of prolyl-peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor Rad52 for viability. We find that FKBP25’s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.

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Summers, K. C., F. Shen, E. A. Sierra Potchanant, E. A. Phipps, R. J. Hickey, and L. H. Malkas. "Phosphorylation: The Molecular Switch of Double-Strand Break Repair." International Journal of Proteomics 2011 (May 18, 2011): 1–8. http://dx.doi.org/10.1155/2011/373816.

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Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.

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23

West, C. E., W. M. Waterworth, P. A. Sunderland, and C. M. Bray. "Arabidopsis DNA double-strand break repair pathways." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 964–66. http://dx.doi.org/10.1042/bst0320964.

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DSBs (double-strand breaks) are one of the most serious forms of DNA damage that can occur in a cell's genome. DNA replication in cells containing DSBs, or following incorrect repair, may result in the loss of large amounts of genetic material, aneuploid daughter cells and cell death. There are two major pathways for DSB repair: HR (homologous recombination) uses an intact copy of the damaged region as a template for repair, whereas NHEJ (non-homologous end-joining) rejoins DNA ends independently of DNA sequence. In most plants, NHEJ is the predominant DSB repair pathway. Previously, the Arabidopsis NHEJ mutant atku80 was isolated and found to display hypersensitivity to bleomycin, a drug that causes DSBs in DNA. In the present study, the transcript profiles of wild-type and atku80 mutant plants grown in the presence and absence of bleomycin are determined by microarray analysis. Several genes displayed very strong transcriptional induction specifically in response to DNA damage, including the characterized DSB repair genes AtRAD51 and AtBRCA1. These results identify novel candidate genes that encode components of the DSB repair pathways active in NHEJ mutant plants.

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Hsu, D. W., R. Kiely, C. A. M. Couto, H. Y. Wang, J. J. R. Hudson, C. Borer, C. J. Pears, and N. D. Lakin. "DNA double-strand break repair pathway choice in Dictyostelium." Journal of Cell Science 124, no. 10 (May 2, 2011): 1655–63. http://dx.doi.org/10.1242/jcs.081471.

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Shrivastav, Meena, Leyma P. De Haro, and Jac A. Nickoloff. "Regulation of DNA double-strand break repair pathway choice." Cell Research 18, no. 1 (December 24, 2007): 134–47. http://dx.doi.org/10.1038/cr.2007.111.

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Aparicio, Tomas, Richard Baer, and Jean Gautier. "DNA double-strand break repair pathway choice and cancer." DNA Repair 19 (July 2014): 169–75. http://dx.doi.org/10.1016/j.dnarep.2014.03.014.

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Nowsheen, Somaira, Min Deng, and Zhenkun Lou. "Ubiquitin and the DNA double-strand break repair pathway." Genome Instability & Disease 1, no. 2 (September 19, 2019): 69–80. http://dx.doi.org/10.1007/s42764-019-00007-5.

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Murray, Johanne M., Tom Stiff, and Penny A. Jeggo. "DNA double-strand break repair within heterochromatic regions." Biochemical Society Transactions 40, no. 1 (January 19, 2012): 173–78. http://dx.doi.org/10.1042/bst20110631.

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DNA DSBs (double-strand breaks) represent a critical lesion for a cell, with misrepair being potentially as harmful as lack of repair. In mammalian cells, DSBs are predominantly repaired by non-homologous end-joining or homologous recombination. The kinetics of repair of DSBs can differ widely, and recent studies have shown that the higher-order chromatin structure can dramatically affect the pathway utilized, the rate of repair and the genetic factors required for repair. Studies of the repair of DSBs arising within heterochromatic DNA regions have provided insight into the constraints that higher-order chromatin structure poses on repair and the processing that is uniquely required for the repair of such DSBs. In the present paper, we provide an overview of our current understanding of the process of heterochromatic DSB repair in mammalian cells and consider the evolutionary conservation of the processes.

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Nick McElhinny, Stephanie A., and Dale A. Ramsden. "Polymerase Mu Is a DNA-Directed DNA/RNA Polymerase." Molecular and Cellular Biology 23, no. 7 (April 1, 2003): 2309–15. http://dx.doi.org/10.1128/mcb.23.7.2309-2315.2003.

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ABSTRACT DNA polymerases are defined as such because they use deoxynucleotides instead of ribonucleotides with high specificity. We show here that polymerase mu (pol μ), implicated in the nonhomologous end-joining pathway for repair of DNA double-strand breaks, incorporates both ribonucleotides and deoxynucleotides in a template-directed manner. pol μ has an approximately 1,000-fold-reduced ability to discriminate against ribonucleotides compared to that of the related pol β, although pol μ's substrate specificity is similar to that of pol β in most other respects. Moreover, pol μ more frequently incorporates ribonucleotides when presented with nucleotide concentrations that approximate cellular pools. We therefore addressed the impact of ribonucleotide incorporation on the activities of factors required for double-strand break repair by nonhomologous end joining. We determined that the ligase required for this pathway readily joined strand breaks with terminal ribonucleotides. Most significantly, pol μ frequently introduced ribonucleotides into the repair junctions of an in vitro nonhomologous end-joining reaction, an activity that would be expected to have important consequences in the context of cellular double-strand break repair.

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Sallmyr, Annahita, та Feyruz V. Rassool. "Up-Regulated WRN and DNA Ligase IIIα Are Involved in Alternative NHEJ Repair Pathway of DNA Double Strand Breaks (DSB) in Chronic Myeloid Leukemia (CML)." Blood 110, № 11 (16 листопада 2007): 1016. http://dx.doi.org/10.1182/blood.v110.11.1016.1016.

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Abstract The oncogenic BCR-ABL in CML produces increased reactive oxygen species (ROS) leading to DSB and aberrant repair. We have previously shown that CML cells demonstrate an increased frequency of errors of non homologous end-joining (NHEJ). DSB are repaired by two major pathways, homologous recombination (HR) and NHEJ, the dominant pathway in eukaryotic cells, also known as DNA-PK dependent NHEJ (D-NHEJ). Recent reports have identified alternative or “back-up” NHEJ pathways (B-NHEJ) that are highly error-prone, and may explain the altered DSB repair reported in CML. To determine the mechanism for the aberrant NHEJ repair in CML, we examined steady state levels of D-NHEJ proteins, including Ku70/86, DNA-PKcs, Artemis and DNA Ligase IV/XRCC4 in four different BCR-ABL positive CML cell lines compared with three lymphoblastoid cell lines established from normal individuals and one BCR-ABL negative CML cell line. We find that two key components of D-NHEJ, Artemis (4–7 fold) and DNA Ligase IV (2–3 fold) are down-regulated, compared with controls. These data suggest that D-NHEJ repair is compromised in CML. To determine whether alternative NHEJ repair plays a role in the aberrant repair of DSB in CML cells, we next examined expression levels of DNA Ligase IIIα/XRCC1, PARP and other proteins known to be associated with NHEJ repair, such as the protein found to be deleted in Werner’s syndrome, WRN. We find that WRN and DNA Ligase IIIα are increased (3–6 fold) in BCR-ABL-positive CML compared with control cell lines. Importantly, DNA Ligase IIIα/XRCC1 forms a complex with WRN, suggesting that it may be a new member of the alternative repair pathway. To confirm that up-regulation of DNA Ligase IIIα and WRN are elicited by BCR-ABL, we examined the levels of these proteins in primary samples (N=4) from patients with different levels of BCR-ABL, following treatment with the tyrosine kinase inhibitor Gleevec. WRN and DNA Ligase IIIα are down regulated in patient samples where BCR-ABL levels are significantly decreased. Furthermore, we confirmed that these up-regulated proteins are involved in DSB repair in CML cells because they co-localize to induced DSB in BCR-ABL-positive cell lines stably transfected with DSB-containing DRneo plasmid, using fluorescence in situ hybridization (FISH) co-immunostaining. Importantly we show that siRNA down-regulation of WRN and DNA Ligase IIIα leads to elevated levels of unrepaired DSB and a decreased frequency of DSB repair efficiency in CML cells. In addition siRNA down-regulation of WRN leads to large deletions at the site of repair, while siRNA down-regulation of DNA Ligase IIIα results in an increased frequency of misrepair. Finally, we determined whether “correction” of main NHEJ pathway proteins in CML can lead to a decrease in the frequency of errors of end-joining repair. Over-expression of Artemis using pcDNA constructs in CML cells leads to more correct end-joining, compared with vector transfected controls. We conclude that down-regulation of Artemis and DNA Ligase IV leads to compensatory up-regulation of alternative repair pathways in BCR-ABL-positive CML cells, and suggest a role for a new protein complex in CML, in protecting and joining DNA ends, thus ensuring the survival of CML cells. Inhibition of alternative NHEJ repair may be explored in combination with other agents as a therapeutic strategy in CML.

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Xu, Yixi, and Dongyi Xu. "Repair pathway choice for double-strand breaks." Essays in Biochemistry 64, no. 5 (July 10, 2020): 765–77. http://dx.doi.org/10.1042/ebc20200007.

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Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

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Yokochi, T., K. Kusano, and I. Kobayashi. "Evidence for conservative (two-progeny) DNA double-strand break repair." Genetics 139, no. 1 (January 1, 1995): 5–17. http://dx.doi.org/10.1093/genetics/139.1.5.

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Abstract The double-strand break repair models for homologous recombination propose that a double-strand break in a duplex DNA segment is repaired by gene conversion copying a homologous DNA segment. This is a type of conservative recombination, or two-progeny recombination, which generates two duplex DNA segments from two duplex DNA segments. Transformation with a plasmid carrying a double-strand gap and an intact homologous DNA segment resulted in products expected from such conservative (two-progeny) repair in Escherichia coli cells with active E. coli RecE pathway (recBC sbcA) or with active bacteriophage lambda Red pathway. Apparently conservative double-strand break repair, however, might result from successive events of nonconservative recombination, or one-progeny recombination, which generates only one recombinant duplex DNA segment from two segments, involving multiple plasmid molecules. Contribution of such intermolecular recombination was evaluated by transformation with a mixture of two isogenic parental plasmids marked with a restriction site polymorphism. Most of the gap repair products were from intramolecular and, therefore, conservative (two-progeny) reaction under the conditions chosen. Most were conservative even in the absence of RecA protein. The double-strand gap repair reaction was not affected by inversion of the unidirectional replication origin on the plasmid. These results demonstrate the presence of the conservative (two-progeny) double-strand break repair mechanism. These experiments do not rule out the occurrence of nonconservative (one-progeny) recombination since we set up experimental conditions that should favor detection of conservative (two-progeny) recombination.

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Legrand, Melanie, Christine L. Chan, Peter A. Jauert, and David T. Kirkpatrick. "Role of DNA Mismatch Repair and Double-Strand Break Repair in Genome Stability and Antifungal Drug Resistance in Candida albicans." Eukaryotic Cell 6, no. 12 (October 26, 2007): 2194–205. http://dx.doi.org/10.1128/ec.00299-07.

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ABSTRACT Drug resistance has become a major problem in the treatment of Candida albicans infections. Genome changes, such as aneuploidy, translocations, loss of heterozygosity, or point mutations, are often observed in clinical isolates that have become resistant to antifungal drugs. To determine whether these types of alterations result when DNA repair pathways are eliminated, we constructed yeast strains bearing deletions in six genes involved in mismatch repair (MSH2 and PMS1) or double-strand break repair (MRE11, RAD50, RAD52, and YKU80). We show that the mre11Δ/mre11Δ, rad50Δ/rad50Δ, and rad52Δ/rad52Δ mutants are slow growing and exhibit a wrinkly colony phenotype and that cultures of these mutants contain abundant elongated pseudohypha-like cells. These same mutants are susceptible to hydrogen peroxide, tetrabutyl hydrogen peroxide, UV radiation, camptothecin, ethylmethane sulfonate, and methylmethane sulfonate. The msh2Δ/msh2Δ, pms1Δ/pms1Δ, and yku80Δ/yku80Δ mutants exhibit none of these phenotypes. We observed an increase in genome instability in mre11Δ/mre11Δ and rad50Δ/rad50Δ mutants by using a GAL1/URA3 marker system to monitor the integrity of chromosome 1. We investigated the acquisition of drug resistance in the DNA repair mutants and found that deletion of mre11Δ/mre11Δ, rad50Δ/rad50Δ, or rad52Δ/rad52Δ leads to an increased susceptibility to fluconazole. Interestingly, we also observed an elevated frequency of appearance of drug-resistant colonies for both msh2Δ/msh2Δ and pms1Δ/pms1Δ (MMR mutants) and rad50Δ/rad50Δ (DSBR mutant). Our data demonstrate that defects in double-strand break repair lead to an increase in genome instability, while drug resistance arises more rapidly in C. albicans strains lacking mismatch repair proteins or proteins central to double-strand break repair.

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Takahashi, Noriko K., Keiko Sakagami, Kohji Kusano, Kenji Yamamoto, Hiroshi Yoshikura, and Ichizo Kobayashi. "Genetic Recombination Through Double-Strand Break Repair: Shift From Two-Progeny Mode to One-Progeny Mode by Heterologous Inserts." Genetics 146, no. 1 (May 1, 1997): 9–26. http://dx.doi.org/10.1093/genetics/146.1.9.

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Double-strand break repair models of genetic recombination propose that a double-strand break is introduced into an otherwise intact DNA and that the break is then repaired by copying a homologous DNA segment. Evidence for these models has been found among lambdoid phages and during yeast meiosis. In an earlier report, we demonstrated such repair of a preformed double-strand break by the Escherichia coli RecE pathway. Here, our experiments with plasmids demonstrate that such reciprocal or conservative recombination (two parental DNAs resulting in two progeny DNAs) is frequent at a double-strand break even when there exists the alternative route of nonreciprocal or nonconservative recombination (two parental DNAs resulting in only one progeny DNA). The presence of a long heterologous DNA at the double-strand break, however, resulted in a shift from the conservative (two-progeny) mode to the nonconservative (one-progeny) mode. The product is a DNA free from the heterologous insert containing recombinant flanking sequences. The potential ability of the homologydependent double-strand break repair reaction to detect and eliminate heterologous inserts may have contributed to the evolution of homologous recombination, meiosis and sexual reproduction.

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35

Li, Jing, and Xingzhi Xu. "DNA double-strand break repair: a tale of pathway choices." Acta Biochimica et Biophysica Sinica 48, no. 7 (May 23, 2016): 641–46. http://dx.doi.org/10.1093/abbs/gmw045.

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36

Davis, Luther, and Nancy Maizels. "Homology-directed repair of DNA nicks via pathways distinct from canonical double-strand break repair." Proceedings of the National Academy of Sciences 111, no. 10 (February 20, 2014): E924—E932. http://dx.doi.org/10.1073/pnas.1400236111.

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DNA nicks are the most common form of DNA damage, and if unrepaired can give rise to genomic instability. In human cells, nicks are efficiently repaired via the single-strand break repair pathway, but relatively little is known about the fate of nicks not processed by that pathway. Here we show that homology-directed repair (HDR) at nicks occurs via a mechanism distinct from HDR at double-strand breaks (DSBs). HDR at nicks, but not DSBs, is associated with transcription and is eightfold more efficient at a nick on the transcribed strand than at a nick on the nontranscribed strand. HDR at nicks can proceed by a pathway dependent upon canonical HDR factors RAD51 and BRCA2; or by an efficient alternative pathway that uses either ssDNA or nicked dsDNA donors and that is strongly inhibited by RAD51 and BRCA2. Nicks generated by either I-AniI or the CRISPR/Cas9D10A nickase are repaired by the alternative HDR pathway with little accompanying mutagenic end-joining, so this pathway may be usefully applied to genome engineering. These results suggest that alternative HDR at nicks may be stimulated in physiological contexts in which canonical RAD51/BRCA2-dependent HDR is compromised or down-regulated, which occurs frequently in tumors.

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Burgess, Joshua T., Chee Man Cheong, Amila Suraweera, Thais Sobanski, Sam Beard, Keyur Dave, Maddison Rose, et al. "Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity." Nucleic Acids Research 49, no. 6 (February 28, 2021): 3294–307. http://dx.doi.org/10.1093/nar/gkab110.

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AbstractDNA repair pathways are essential to maintain the integrity of the genome and prevent cell death and tumourigenesis. Here, we show that the Barrier-to-Autointegration Factor (Banf1) protein has a role in the repair of DNA double-strand breaks. Banf1 is characterized as a nuclear envelope protein and mutations in Banf1 are associated with the severe premature aging syndrome, Néstor–Guillermo Progeria Syndrome. We have previously shown that Banf1 directly regulates the activity of PARP1 in the repair of oxidative DNA lesions. Here, we show that Banf1 also has a role in modulating DNA double-strand break repair through regulation of the DNA-dependent Protein Kinase catalytic subunit, DNA-PKcs. Specifically, we demonstrate that Banf1 relocalizes from the nuclear envelope to sites of DNA double-strand breaks. We also show that Banf1 can bind to and directly inhibit the activity of DNA-PKcs. Supporting this, cellular depletion of Banf1 leads to an increase in non-homologous end-joining and a decrease in homologous recombination, which our data suggest is likely due to unrestrained DNA-PKcs activity. Overall, this study identifies how Banf1 regulates double-strand break repair pathway choice by modulating DNA-PKcs activity to control genome stability within the cell.

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38

Karamouzis, M. V., C. Mihailidou, P. Papakotoulas, A. Anestis, E. Koustas, and A. G. Papavassiliou. "Targeting c-met and DNA double-strand break (DSB) repair pathways for BRCA-mutated gastric carcinomas." Annals of Oncology 28 (September 2017): v233. http://dx.doi.org/10.1093/annonc/mdx369.068.

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39

Gomez-Cabello, Daniel, Sonia Jimeno, María Jesús Fernández-Ávila, and Pablo Huertas. "New Tools to Study DNA Double-Strand Break Repair Pathway Choice." PLoS ONE 8, no. 10 (October 14, 2013): e77206. http://dx.doi.org/10.1371/journal.pone.0077206.

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40

Guo, Xiang, Yongtai Bai, Meimei Zhao, Mei Zhou, Qinjian Shen, Cai-Hong Yun, Hongquan Zhang, Wei-Guo Zhu, and Jiadong Wang. "Acetylation of 53BP1 dictates the DNA double strand break repair pathway." Nucleic Acids Research 46, no. 2 (November 28, 2017): 689–703. http://dx.doi.org/10.1093/nar/gkx1208.

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Chapman, J. Ross, Martin R. G. Taylor, and Simon J. Boulton. "Playing the End Game: DNA Double-Strand Break Repair Pathway Choice." Molecular Cell 47, no. 4 (August 2012): 497–510. http://dx.doi.org/10.1016/j.molcel.2012.07.029.

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Scully, Ralph, Arvind Panday, Rajula Elango, and Nicholas A. Willis. "DNA double-strand break repair-pathway choice in somatic mammalian cells." Nature Reviews Molecular Cell Biology 20, no. 11 (July 1, 2019): 698–714. http://dx.doi.org/10.1038/s41580-019-0152-0.

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Clouaire, T., and G. Legube. "DNA double strand break repair pathway choice: a chromatin based decision?" Nucleus 6, no. 2 (February 12, 2015): 107–13. http://dx.doi.org/10.1080/19491034.2015.1010946.

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44

Li, Jinbao, Huize Sun, Yulin Huang, Yali Wang, Yuyan Liu, and Xuefeng Chen. "Pathways and assays for DNA double-strand break repair by homologous recombination." Acta Biochimica et Biophysica Sinica 51, no. 9 (July 10, 2019): 879–89. http://dx.doi.org/10.1093/abbs/gmz076.

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AbstractDouble strand breaks (DSBs) are the most detrimental type of DNA damage that must be repaired to ensure genome integrity and cell survival. Unrepaired or improperly repaired DSBs can potentially cause tumorigenesis or cell death. DSBs are primarily repaired by non-homologous end joining or homologous recombination (HR). The HR pathway is initiated by processing of the 5′-end of DSBs to generate 3′-end single-strand DNA (ssDNA). Furthermore, the intermediate is channeled to one of the HR sub-pathways, including: (i) double Holliday junction (dHJ) pathway, (ii) synthesis-dependent strand annealing (SDSA), (iii) break-induced replication (BIR), and (iv) single-strand annealing (SSA). In the dHJ sub-pathway, the 3′-ssDNA coated with Rad51 recombinase performs homology search and strand invasion, forming a displacement loop (D-loop). Capture of the second end by the D-loop generates a dHJ intermediate that is subsequently dissolved by DNA helicase or resolved by nucleases, producing non-crossover or crossover products. In SDSA, the newly synthesized strand is displaced from the D-loop and anneals to the end on the other side of the DSBs, producing non-crossovers. In contrast, BIR repairs one-end DSBs by copying the sequence up to the end of the template chromosome, resulting in translocation or loss of heterozygosity. SSA takes place when resection reveals flanking homologous repeats that can anneal, leading to deletion of the intervening sequences. A variety of reporter assays have been developed to monitor distinct HR sub-pathways in both Saccharomyces cerevisiae and mammals. Here, we summarize the principles and representative assays for different HR sub-pathways with an emphasis on the studies in the budding yeast.

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Hartlerode, Andrea J., and Ralph Scully. "Mechanisms of double-strand break repair in somatic mammalian cells." Biochemical Journal 423, no. 2 (September 25, 2009): 157–68. http://dx.doi.org/10.1042/bj20090942.

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DNA chromosomal DSBs (double-strand breaks) are potentially hazardous DNA lesions, and their accurate repair is essential for the successful maintenance and propagation of genetic information. Two major pathways have evolved to repair DSBs: HR (homologous recombination) and NHEJ (non-homologous end-joining). Depending on the context in which the break is encountered, HR and NHEJ may either compete or co-operate to fix DSBs in eukaryotic cells. Defects in either pathway are strongly associated with human disease, including immunodeficiency and cancer predisposition. Here we review the current knowledge of how NHEJ and HR are controlled in somatic mammalian cells, and discuss the role of the chromatin context in regulating each pathway. We also review evidence for both co-operation and competition between the two pathways.

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Yan, Hong, Jill McCane, Thomas Toczylowski, and Chinyi Chen. "Analysis of the Xenopus Werner syndrome protein in DNA double-strand break repair." Journal of Cell Biology 171, no. 2 (October 24, 2005): 217–27. http://dx.doi.org/10.1083/jcb.200502077.

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Werner syndrome is associated with premature aging and increased risk of cancer. Werner syndrome protein (WRN) is a RecQ-type DNA helicase, which seems to participate in DNA replication, double-strand break (DSB) repair, and telomere maintenance; however, its exact function remains elusive. Using Xenopus egg extracts as the model system, we found that Xenopus WRN (xWRN) is recruited to discrete foci upon induction of DSBs. Depletion of xWRN has no significant effect on nonhomologous end-joining of DSB ends, but it causes a significant reduction in the homology-dependent single-strand annealing DSB repair pathway. These results provide the first direct biochemical evidence that links WRN to a specific DSB repair pathway. The assay for single-strand annealing that was developed in this study also provides a powerful biochemical system for mechanistic analysis of homology-dependent DSB repair.

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Paliwal, Shreya, Radhakrishnan Kanagaraj, Andreas Sturzenegger, Kamila Burdova, and Pavel Janscak. "Human RECQ5 helicase promotes repair of DNA double-strand breaks by synthesis-dependent strand annealing." Nucleic Acids Research 42, no. 4 (December 5, 2013): 2380–90. http://dx.doi.org/10.1093/nar/gkt1263.

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Abstract Most mitotic homologous recombination (HR) events proceed via a synthesis-dependent strand annealing mechanism to avoid crossing over, which may give rise to chromosomal rearrangements and loss of heterozygosity. The molecular mechanisms controlling HR sub-pathway choice are poorly understood. Here, we show that human RECQ5, a DNA helicase that can disrupt RAD51 nucleoprotein filaments, promotes formation of non-crossover products during DNA double-strand break-induced HR and counteracts the inhibitory effect of RAD51 on RAD52-mediated DNA annealing in vitro and in vivo. Moreover, we demonstrate that RECQ5 deficiency is associated with an increased occupancy of RAD51 at a double-strand break site, and it also causes an elevation of sister chromatid exchanges on inactivation of the Holliday junction dissolution pathway or on induction of a high load of DNA damage in the cell. Collectively, our findings suggest that RECQ5 acts during the post-synaptic phase of synthesis-dependent strand annealing to prevent formation of aberrant RAD51 filaments on the extended invading strand, thus limiting its channeling into potentially hazardous crossover pathway of HR.

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Hooshyar, Mohsen, Daniel Burnside, Maryam Hajikarimlou, Katayoun Omidi, Alexander Jesso, Megan Vanstone, Adamo Young, et al. "Actin-Related Protein 6 (Arp6) Influences Double-Strand Break Repair in Yeast." Applied Microbiology 1, no. 2 (July 16, 2021): 225–38. http://dx.doi.org/10.3390/applmicrobiol1020017.

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DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

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Dang, Tuyen T., and Julio C. Morales. "XRN2 Links RNA:DNA Hybrid Resolution to Double Strand Break Repair Pathway Choice." Cancers 12, no. 7 (July 7, 2020): 1821. http://dx.doi.org/10.3390/cancers12071821.

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It was recently shown that the 5’ to 3’ exoribonuclease XRN2 is involved in the DNA damage response. Importantly, loss of XRN2 abrogates DNA double stranded break repair via the non-homologous end-joining pathway. However, the mechanistic details of how XRN2 functions in the non-homologous end-joining repair process are unknown. In this study, we elucidated that XRN2-mediated RNA:DNA hybrid resolution is required to allow Ku70 binding to DNA ends. These data suggest that XRN2 is required for the initiation of non-homologous end-joining repair. Interestingly, we uncovered a role for XRN2 in the homologous recombination repair pathway. Loss of XRN2 lead to a decrease in the repair of double strand breaks by homologous recombination. Strikingly, when we removed RNA:DNA hybrids by RNaseH1 over-expression, homologous recombination was not restored. We found RNA:DNA hybrid formation at and downstream of the DSB site, suggesting that unregulated transcription inhibits homologous recombination repair. In summary, our results indicate a relation between RNA:DNA hybrid resolution and double strand break repair pathway choice.

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Stahl-Rommel, Sarah, David Li, Michelle Sung, Rebecca Li, Aarthi Vijayakumar, Kutay Deniz Atabay, G. Guy Bushkin, et al. "A CRISPR-based assay for the study of eukaryotic DNA repair onboard the International Space Station." PLOS ONE 16, no. 6 (June 30, 2021): e0253403. http://dx.doi.org/10.1371/journal.pone.0253403.

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As we explore beyond Earth, astronauts may be at risk for harmful DNA damage caused by ionizing radiation. Double-strand breaks are a type of DNA damage that can be repaired by two major cellular pathways: non-homologous end joining, during which insertions or deletions may be added at the break site, and homologous recombination, in which the DNA sequence often remains unchanged. Previous work suggests that space conditions may impact the choice of DNA repair pathway, potentially compounding the risks of increased radiation exposure during space travel. However, our understanding of this problem has been limited by technical and safety concerns, which have prevented integral study of the DNA repair process in space. The CRISPR/Cas9 gene editing system offers a model for the safe and targeted generation of double-strand breaks in eukaryotes. Here we describe a CRISPR-based assay for DNA break induction and assessment of double-strand break repair pathway choice entirely in space. As necessary steps in this process, we describe the first successful genetic transformation and CRISPR/Cas9 genome editing in space. These milestones represent a significant expansion of the molecular biology toolkit onboard the International Space Station.

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