Journal articles: 'Genome damage'

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Proshkina, Ekaterina, Mikhail Shaposhnikov, and Alexey Moskalev. "Genome-Protecting Compounds as Potential Geroprotectors." International Journal of Molecular Sciences 21, no. 12 (June 24, 2020): 4484. http://dx.doi.org/10.3390/ijms21124484.

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Throughout life, organisms are exposed to various exogenous and endogenous factors that cause DNA damages and somatic mutations provoking genomic instability. At a young age, compensatory mechanisms of genome protection are activated to prevent phenotypic and functional changes. However, the increasing stress and age-related deterioration in the functioning of these mechanisms result in damage accumulation, overcoming the functional threshold. This leads to aging and the development of age-related diseases. There are several ways to counteract these changes: (1) prevention of DNA damage through stimulation of antioxidant and detoxification systems, as well as transition metal chelation; (2) regulation of DNA methylation, chromatin structure, non-coding RNA activity and prevention of nuclear architecture alterations; (3) improving DNA damage response and repair; (4) selective removal of damaged non-functional and senescent cells. In the article, we have reviewed data about the effects of various trace elements, vitamins, polyphenols, terpenes, and other phytochemicals, as well as a number of synthetic pharmacological substances in these ways. Most of the compounds demonstrate the geroprotective potential and increase the lifespan in model organisms. However, their genome-protecting effects are non-selective and often are conditioned by hormesis. Consequently, the development of selective drugs targeting genome protection is an advanced direction.

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Henkel, Ralf R., and Daniel R. Franken. "Sperm DNA Fragmentation: Origin and Impact on Human Reproduction." Journal of Reproductive and Stem Cell Biotechnology 2, no. 2 (December 2011): 88–108. http://dx.doi.org/10.1177/205891581100200204.

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Sperm DNA can be damaged due to a multitude of different noxae, which include disease, and occupational and environmental factors. Depending on the magnitude of the damage, such lesions may be repaired by the oocyte or the embryo. If this is not possible, a permanent damage can be manifested leading to mutations of the male genome. In cases where the oocyte or the embryo does not counter these damages to the male genome in terms of repair or an early abortion, sperm DNA damage and fragmentation can be a cause of numerous diseases including childhood cancer.

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LIU, Wei-Feng, Shan-Shan YU, Guan-Jun CHEN, and Yue-Zhong LI. "DNA Damage Checkpoint, Damage Repair, and Genome Stability." Acta Genetica Sinica 33, no. 5 (May 2006): 381–90. http://dx.doi.org/10.1016/s0379-4172(06)60064-4.

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Alhegaili, Alaa S., Yunhee Ji, Nicolas Sylvius, Matthew J. Blades, Mahsa Karbaschi, Helen G. Tempest, George D. D. Jones, and Marcus S. Cooke. "Genome-Wide Adductomics Analysis Reveals Heterogeneity in the Induction and Loss of Cyclobutane Thymine Dimers across Both the Nuclear and Mitochondrial Genomes." International Journal of Molecular Sciences 20, no. 20 (October 15, 2019): 5112. http://dx.doi.org/10.3390/ijms20205112.

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The distribution of DNA damage and repair is considered to occur heterogeneously across the genome. However, commonly available techniques, such as the alkaline comet assay or HPLC-MS/MS, measure global genome levels of DNA damage, and do not reflect potentially significant events occurring at the gene/sequence-specific level, in the nuclear or mitochondrial genomes. We developed a method, which comprises a combination of Damaged DNA Immunoprecipitation and next generation sequencing (DDIP-seq), to assess the induction and repair of DNA damage induced by 0.1 J/cm2 solar-simulated radiation at the sequence-specific level, across both the entire nuclear and mitochondrial genomes. DDIP-seq generated a genome-wide, high-resolution map of cyclobutane thymine dimer (T<>T) location and intensity. In addition to being a straightforward approach, our results demonstrated a clear differential distribution of T<>T induction and loss, across both the nuclear and mitochondrial genomes. For nuclear DNA, this differential distribution existed at both the sequence and chromosome level. Levels of T<>T were much higher in the mitochondrial DNA, compared to nuclear DNA, and decreased with time, confirmed by qPCR, despite no reported mechanisms for their repair in this organelle. These data indicate the existence of regions of sensitivity and resistance to damage formation, together with regions that are fully repaired, and those for which > 90% of damage remains, after 24 h. This approach offers a simple, yet more detailed approach to studying cellular DNA damage and repair, which will aid our understanding of the link between DNA damage and disease.

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Ferrand, Juliette, Beatrice Rondinelli, and Sophie E. Polo. "Histone Variants: Guardians of Genome Integrity." Cells 9, no. 11 (November 5, 2020): 2424. http://dx.doi.org/10.3390/cells9112424.

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Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field.

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Thomas, Mark, Gaetan Burgio, David J. Adams, and Vivek Iyer. "Collateral damage and CRISPR genome editing." PLOS Genetics 15, no. 3 (March 14, 2019): e1007994. http://dx.doi.org/10.1371/journal.pgen.1007994.

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Petruseva, I. O., A. N. Evdokimov, and O. I. Lavrik. "Molecular Mechanism of Global Genome Nucleotide Excision Repair." Acta Naturae 6, no. 1 (March 15, 2014): 23–34. http://dx.doi.org/10.32607/20758251-2014-6-1-23-34.

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Nucleotide excision repair (NER) is a multistep process that recognizes and eliminates a wide spectrum of damage causing significant distortions in the DNA structure, such as UV-induced damage and bulky chemical adducts. The consequences of defective NER are apparent in the clinical symptoms of individuals affected by three disorders associated with reduced NER capacities: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). These disorders have in common increased sensitivity to UV irradiation, greatly elevated cancer incidence (XP), and multi-system immunological and neurological disorders. The eucaryotic NER system eliminates DNA damage by the excision of 24-32 nt single-strand oligonucleotides from a damaged strand, followed by restoration of an intact double helix by DNA repair synthesis and DNA ligation. About 30 core polypeptides are involved in the entire repair process. NER consists of two pathways distinct in initial damage sensor proteins: transcription-coupled repair (TC-NER) and global genome repair (GG-NER). The article reviews current knowledge on the molecular mechanisms underlying damage recognition and its elimination from mammalian DNA.

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Trakhtenberg, I. M., Y. I. Gubsky, E. L. Levitsky, and I. F. Belenichev. "Biochemical mechanisms of free-radical damage to the nuclear genome by cadmium." Ukrainian Biochemical Journal 90, no. 3 (June 25, 2018): 5–16. http://dx.doi.org/10.15407/ubj90.03.005.

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Collura, Ada, Joel Blaisonneau, Giuseppe Baldacci, and Stefania Francesconi. "The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7889–99. http://dx.doi.org/10.1128/mcb.25.17.7889-7899.2005.

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ABSTRACT Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase I, the Chk1 DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G2/M DNA damage checkpoint.

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Hu, Jinchuan, Jason D. Lieb, Aziz Sancar, and Sheera Adar. "Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution." Proceedings of the National Academy of Sciences 113, no. 41 (September 29, 2016): 11507–12. http://dx.doi.org/10.1073/pnas.1614430113.

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Cisplatin is a major anticancer drug that kills cancer cells by damaging their DNA. Cancer cells cope with the drug by removal of the damages with nucleotide excision repair. We have developed methods to measure cisplatin adduct formation and its repair at single-nucleotide resolution. “Damage-seq” relies on the replication-blocking properties of the bulky base lesions to precisely map their location. “XR-seq” independently maps the removal of these damages by capturing and sequencing the excised oligomer released during repair. The damage and repair maps we generated reveal that damage distribution is essentially uniform and is dictated mostly by the underlying sequence. In contrast, cisplatin repair is heterogeneous in the genome and is affected by multiple factors including transcription and chromatin states. Thus, the overall effect of damages in the genome is primarily driven not by damage formation but by the repair efficiency. The combination of the Damage-seq and XR-seq methods has the potential for developing novel cancer therapeutic strategies.

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Takatsuka, Hirotomo, Atsushi Shibata, and Masaaki Umeda. "Genome Maintenance Mechanisms at the Chromatin Level." International Journal of Molecular Sciences 22, no. 19 (September 27, 2021): 10384. http://dx.doi.org/10.3390/ijms221910384.

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Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

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Middelkamp, Sjors, Helena T. A. van Tol, Diana C. J. Spierings, Sander Boymans, Victor Guryev, Bernard A. J. Roelen, Peter M. Lansdorp, Edwin Cuppen, and Ewart W. Kuijk. "Sperm DNA damage causes genomic instability in early embryonic development." Science Advances 6, no. 16 (April 2020): eaaz7602. http://dx.doi.org/10.1126/sciadv.aaz7602.

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Genomic instability is common in human embryos, but the underlying causes are largely unknown. Here, we examined the consequences of sperm DNA damage on the embryonic genome by single-cell whole-genome sequencing of individual blastomeres from bovine embryos produced with sperm damaged by γ-radiation. Sperm DNA damage primarily leads to fragmentation of the paternal chromosomes followed by random distribution of the chromosomal fragments over the two sister cells in the first cell division. An unexpected secondary effect of sperm DNA damage is the induction of direct unequal cleavages, which include the poorly understood heterogoneic cell divisions. As a result, chaotic mosaicism is common in embryos derived from fertilizations with damaged sperm. The mosaic aneuploidies, uniparental disomies, and de novo structural variation induced by sperm DNA damage may compromise fertility and lead to rare congenital disorders when embryos escape developmental arrest.

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Bowater, Richard P., Rhona H. Borts, and Malcolm F. White. "DNA Damage: from Causes to Cures." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 479–81. http://dx.doi.org/10.1042/bst0370479.

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In order to maintain genome integrity, it is essential that any DNA damage is repaired. This is achieved in diverse ways in all cells to ensure cellular survival. There is a large repertoire of proteins that remove and repair DNA damage. However, sometimes these processes do not function correctly, leading to genome instability. Studies of DNA repair and genome instability and their causes and cures were showcased in the 2008 Biochemical Society Annual Symposium. The present article provides a summary of the talks given and the subsequent papers in this issue of Biochemical Society Transactions.

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Farkash, Evan A., and Eline T. Luning Prak. "DNA Damage and L1 Retrotransposition." Journal of Biomedicine and Biotechnology 2006 (2006): 1–8. http://dx.doi.org/10.1155/jbb/2006/37285.

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Barbara McClintock was the first to suggest that transposons are a source of genome instability and that genotoxic stress assisted in their mobilization. The generation of double-stranded DNA breaks (DSBs) is a severe form of genotoxic stress that threatens the integrity of the genome, activates cell cycle checkpoints, and, in some cases, causes cell death. Applying McClintock's stress hypothesis to humans, are L1 retrotransposons, the most active autonomous mobile elements in the modern day human genome, mobilized by DSBs? Here, evidence that transposable elements, particularly retrotransposons, are mobilized by genotoxic stress is reviewed. In the setting of DSB formation, L1 mobility may be affected by changes in the substrate for L1 integration, the DNA repair machinery, or the L1 element itself. The review concludes with a discussion of the potential consequences of L1 mobilization in the setting of genotoxic stress.

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Mushtaq, Arjamand, Ulfat Syed Mir, Clayton R. Hunt, Shruti Pandita, Wajahat W. Tantray, Audesh Bhat, Raj K. Pandita, Mohammad Altaf, and Tej K. Pandita. "Role of Histone Methylation in Maintenance of Genome Integrity." Genes 12, no. 7 (June 29, 2021): 1000. http://dx.doi.org/10.3390/genes12071000.

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Packaging of the eukaryotic genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms that are critically dependent upon chromatin structures established by histones and, particularly upon transient histone post-translational modifications. Though subjected to a range of modifications, histone methylation is especially crucial for DNA damage repair, as the methylated histones often form platforms for subsequent repair protein binding at damaged sites. In this review, we highlight and discuss how histone methylation impacts the maintenance of genome integrity through effects related to DNA repair and repair pathway choice.

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Renaud, Gabriel, Kristian Hanghøj, Thorfinn Sand Korneliussen, Eske Willerslev, and Ludovic Orlando. "Joint Estimates of Heterozygosity and Runs of Homozygosity for Modern and Ancient Samples." Genetics 212, no. 3 (May 14, 2019): 587–614. http://dx.doi.org/10.1534/genetics.119.302057.

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Both the total amount and the distribution of heterozygous sites within individual genomes are informative about the genetic diversity of the population they belong to. Detecting true heterozygous sites in ancient genomes is complicated by the generally limited coverage achieved and the presence of post-mortem damage inflating sequencing errors. Additionally, large runs of homozygosity found in the genomes of particularly inbred individuals and of domestic animals can skew estimates of genome-wide heterozygosity rates. Current computational tools aimed at estimating runs of homozygosity and genome-wide heterozygosity levels are generally sensitive to such limitations. Here, we introduce ROHan, a probabilistic method which substantially improves the estimate of heterozygosity rates both genome-wide and for genomic local windows. It combines a local Bayesian model and a Hidden Markov Model at the genome-wide level and can work both on modern and ancient samples. We show that our algorithm outperforms currently available methods for predicting heterozygosity rates for ancient samples. Specifically, ROHan can delineate large runs of homozygosity (at megabase scales) and produce a reliable confidence interval for the genome-wide rate of heterozygosity outside of such regions from modern genomes with a depth of coverage as low as 5–6× and down to 7–8× for ancient samples showing moderate DNA damage. We apply ROHan to a series of modern and ancient genomes previously published and revise available estimates of heterozygosity for humans, chimpanzees and horses.

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Schalk, Catherine, Valérie Cognat, Stéfanie Graindorge, Timothée Vincent, Olivier Voinnet, and Jean Molinier. "Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1." Proceedings of the National Academy of Sciences 114, no. 14 (March 21, 2017): E2965—E2974. http://dx.doi.org/10.1073/pnas.1618834114.

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As photosynthetic organisms, plants need to prevent irreversible UV-induced DNA lesions. Through an unbiased, genome-wide approach, we have uncovered a previously unrecognized interplay between Global Genome Repair and small interfering RNAs (siRNAs) in the recognition of DNA photoproducts, prevalently in intergenic regions. Genetic and biochemical approaches indicate that, upon UV irradiation, the DNA DAMAGE-BINDING PROTEIN 2 (DDB2) and ARGONAUTE 1 (AGO1) of Arabidopsis thaliana form a chromatin-bound complex together with 21-nt siRNAs, which likely facilitates recognition of DNA damages in an RNA/DNA complementary strand-specific manner. The biogenesis of photoproduct-associated siRNAs involves the noncanonical, concerted action of RNA POLYMERASE IV, RNA-DEPENDENT RNA POLYMERASE-2, and DICER-LIKE-4. Furthermore, the chromatin association/dissociation of the DDB2-AGO1 complex is under the control of siRNA abundance and DNA damage signaling. These findings reveal unexpected nuclear functions for DCL4 and AGO1, and shed light on the interplay between small RNAs and DNA repair recognition factors at damaged sites.

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Burgio, Gaëtan, and Lydia Teboul. "Anticipating and Identifying Collateral Damage in Genome Editing." Trends in Genetics 36, no. 12 (December 2020): 905–14. http://dx.doi.org/10.1016/j.tig.2020.09.011.

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Jelluma, Nannette, and Geert J. P. L. Kops. "Collateral Genome Instability by DNA Damage in Mitosis." Cancer Discovery 4, no. 11 (November 2014): 1256–58. http://dx.doi.org/10.1158/2159-8290.cd-14-1097.

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Wu, Qian. "Guardians of the genome: DNA damage and repair." Essays in Biochemistry 64, no. 5 (October 2020): 683–85. http://dx.doi.org/10.1042/ebc20200109.

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Abstract This collection of reviews aims to summarise our current understanding of a fundamental question: how do we deal with DNA damage? After identifying key players that are important for this process, we are now starting to reveal the dynamic organisation of detecting and repairing DNA damage. Reviews in this issue provide an update on the exciting research progress that is happening now in this field and also initiate discussion about future challenges and directions that we are heading to.

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Karran, P., and M. Bignami. "DNA damage tolerance, mismatch repair and genome instability." BioEssays 16, no. 11 (November 1994): 833–39. http://dx.doi.org/10.1002/bies.950161110.

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Akatsuka, Shinya, and Shinya Toyokuni. "Genome-wide assessment of oxidatively generated DNA damage." Free Radical Research 46, no. 4 (February 22, 2012): 523–30. http://dx.doi.org/10.3109/10715762.2011.633212.

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Conticello, Silvestro G. "Creative deaminases, self-inflicted damage, and genome evolution." Annals of the New York Academy of Sciences 1267, no. 1 (September 2012): 79–85. http://dx.doi.org/10.1111/j.1749-6632.2012.06614.x.

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Ljungman, Mats, and David P. Lane. "Transcription — guarding the genome by sensing DNA damage." Nature Reviews Cancer 4, no. 9 (September 2004): 727–37. http://dx.doi.org/10.1038/nrc1435.

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SINGH, K. "Mitochondria damage checkpoint in apoptosis and genome stability." FEMS Yeast Research 5, no. 2 (November 2004): 127–32. http://dx.doi.org/10.1016/j.femsyr.2004.04.008.

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Akatsuka, Shinya, and Shinya Toyokuni. "Genome-Scale Approaches to Investigate Oxidative DNA Damage." Journal of Clinical Biochemistry and Nutrition 47, no. 2 (2010): 91–97. http://dx.doi.org/10.3164/jcbn.10-38r.

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Bakhoum, S., L. Kabeche, M. Wood, A. Suriawinata, R. Louie, D. Chan, C. Petritsch, J. Murnane, D. Compton, and B. Zaki. "A Mitotic Pathway for Radiation-Induced Genome Damage." International Journal of Radiation Oncology*Biology*Physics 87, no. 2 (October 2013): S637. http://dx.doi.org/10.1016/j.ijrobp.2013.06.1684.

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Guo, Weier, Luca Comai, and Isabelle M. Henry. "Chromoanagenesis from radiation-induced genome damage in Populus." PLOS Genetics 17, no. 8 (August 25, 2021): e1009735. http://dx.doi.org/10.1371/journal.pgen.1009735.

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Chromoanagenesis is a genomic catastrophe that results in chromosomal shattering and reassembly. These extreme single chromosome events were first identified in cancer, and have since been observed in other systems, but have so far only been formally documented in plants in the context of haploid induction crosses. The frequency, origins, consequences, and evolutionary impact of such major chromosomal remodeling in other situations remain obscure. Here, we demonstrate the occurrence of chromoanagenesis in poplar (Populus sp.) trees produced from gamma-irradiated pollen. Specifically, in this population of siblings carrying indel mutations, two individuals exhibited highly frequent copy number variation (CNV) clustered on a single chromosome, one of the hallmarks of chromoanagenesis. Using short-read sequencing, we confirmed the presence of clustered segmental rearrangement. Independently, we identified and validated novel DNA junctions and confirmed that they were clustered and corresponded to these rearrangements. Our reconstruction of the novel sequences suggests that the chromosomal segments have reorganized randomly to produce a novel rearranged chromosome but that two different mechanisms might be at play. Our results indicate that gamma irradiation can trigger chromoanagenesis, suggesting that this may also occur when natural or induced mutagens cause DNA breaks. We further demonstrate that such events can be tolerated in poplar, and even replicated clonally, providing an attractive system for more in-depth investigations of their consequences.

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Chiu, Li-Ya, Fade Gong, and Kyle M. Miller. "Bromodomain proteins: repairing DNA damage within chromatin." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1731 (August 28, 2017): 20160286. http://dx.doi.org/10.1098/rstb.2016.0286.

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Genome surveillance and repair, termed the DNA damage response (DDR), functions within chromatin. Chromatin-based DDR mechanisms sustain genome and epigenome integrity, defects that can disrupt cellular homeostasis and contribute to human diseases. An important chromatin DDR pathway is acetylation signalling which is controlled by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, which regulate acetylated lysines within proteins. Acetylated proteins, including histones, can modulate chromatin structure and provide molecular signals that are bound by acetyl-lysine binders, including bromodomain (BRD) proteins. Acetylation signalling regulates several DDR pathways, as exemplified by the preponderance of HATs, HDACs and BRD proteins that localize at DNA breaks to modify chromatin for lesion repair. Here, we explore the involvement of acetylation signalling in the DDR, focusing on the involvement of BRD proteins in promoting chromatin remodelling to repair DNA double-strand breaks. BRD proteins have widespread DDR functions including chromatin remodelling, chromatin modification and transcriptional regulation. We discuss mechanistically how BRD proteins read acetylation signals within chromatin to trigger DDR and chromatin activities to facilitate genome–epigenome maintenance. Thus, DDR pathways involving BRD proteins represent key participants in pathways that preserve genome–epigenome integrity to safeguard normal genome and cellular functions. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

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Mancini, Monica, Elena Magnani, Filippo Macchi, and Ian Marc Bonapace. "The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity." Nucleic Acids Research 49, no. 11 (May 3, 2021): 6053–68. http://dx.doi.org/10.1093/nar/gkab293.

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Abstract During S phase, the cooperation between the macromolecular complexes regulating DNA synthesis, epigenetic information maintenance and DNA repair is advantageous for cells, as they can rapidly detect DNA damage and initiate the DNA damage response (DDR). UHRF1 is a fundamental epigenetic regulator; its ability to coordinate DNA methylation and histone code is unique across proteomes of different species. Recently, UHRF1’s role in DNA damage repair has been explored and recognized to be as important as its role in maintaining the epigenome. UHRF1 is a sensor for interstrand crosslinks and a determinant for the switch towards homologous recombination in the repair of double-strand breaks; its loss results in enhanced sensitivity to DNA damage. These functions are finely regulated by specific post-translational modifications and are mediated by the SRA domain, which binds to damaged DNA, and the RING domain. Here, we review recent studies on the role of UHRF1 in DDR focusing on how it recognizes DNA damage and cooperates with other proteins in its repair. We then discuss how UHRF1’s epigenetic abilities in reading and writing histone modifications, or its interactions with ncRNAs, could interlace with its role in DDR.

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Iyer, Divya Ramalingam, and Nicholas Rhind. "Checkpoint regulation of replication forks: global or local?" Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1701–5. http://dx.doi.org/10.1042/bst20130197.

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Cell-cycle checkpoints are generally global in nature: one unattached kinetochore prevents the segregation of all chromosomes; stalled replication forks inhibit late origin firing throughout the genome. A potential exception to this rule is the regulation of replication fork progression by the S-phase DNA damage checkpoint. In this case, it is possible that the checkpoint is global, and it slows all replication forks in the genome. However, it is also possible that the checkpoint acts locally at sites of DNA damage, and only slows those forks that encounter DNA damage. Whether the checkpoint regulates forks globally or locally has important mechanistic implications for how replication forks deal with damaged DNA during S-phase.

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Kumar, Kundan, Romila Moirangthem, and Rupinder Kaur. "Genome protection: histone H4 and beyond." Current Genetics 66, no. 5 (June 17, 2020): 945–50. http://dx.doi.org/10.1007/s00294-020-01088-6.

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Abstract Histone proteins regulate cellular factors’ accessibility to DNA, and histone dosage has previously been linked with DNA damage susceptibility and efficiency of DNA repair pathways. Surplus histones are known to impede the DNA repair process by interfering with the homologous recombination-mediated DNA repair in Saccharomyces cerevisiae. Here, we discuss the recent finding of association of methyl methanesulfonate (MMS) resistance with the reduced histone H4 gene dosage in the pathogenic yeast Candida glabrata. We have earlier shown that while the low histone H3 gene dosage led to MMS susceptibility, the lack of two H4-encoding ORFs, CgHHF1 and CgHHF2, led to resistance to MMS-induced DNA damage. This resistance was linked with a higher rate of homologous recombination (HR). Taking these findings further, we review the interactome analysis of histones H3 and H4 in C. glabrata. We also report that the arginine residue present at the 95th position in the C-terminal tail of histone H4 protein is required for complementation of the MMS resistance in the Cghhf1Δhhf2Δ mutant, thereby pointing out a probable role of this residue in association with HR factors. Additionally, we present evidence that reduction in H4 protein levels may constitute an important part of varied stress responses in C. glabrata. Altogether, we present an overview of histone H4 dosage, HR-mediated repair of damaged DNA and stress resistance in this opportunistic human fungal pathogen.

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McAvera, Roisin M., and Lisa J. Crawford. "TIF1 Proteins in Genome Stability and Cancer." Cancers 12, no. 8 (July 28, 2020): 2094. http://dx.doi.org/10.3390/cancers12082094.

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Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation.

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Weitzman, Matthew D., and Amélie Fradet-Turcotte. "Virus DNA Replication and the Host DNA Damage Response." Annual Review of Virology 5, no. 1 (September 29, 2018): 141–64. http://dx.doi.org/10.1146/annurev-virology-092917-043534.

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Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host.

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Carusillo, Antonio, and Claudio Mussolino. "DNA Damage: From Threat to Treatment." Cells 9, no. 7 (July 10, 2020): 1665. http://dx.doi.org/10.3390/cells9071665.

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DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

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McVoy, Michael A., and Daniel E. Nixon. "Impact of 2-Bromo-5,6-Dichloro-1-β-d-Ribofuranosyl Benzimidazole Riboside and Inhibitors of DNA, RNA, and Protein Synthesis on Human Cytomegalovirus Genome Maturation." Journal of Virology 79, no. 17 (September 1, 2005): 11115–27. http://dx.doi.org/10.1128/jvi.79.17.11115-11127.2005.

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ABSTRACT Herpesvirus genome maturation is a complex process in which concatemeric DNA molecules are translocated into capsids and cleaved at specific sequences to produce encapsidated-unit genomes. Bacteriophage studies further suggest that important ancillary processes, such as RNA transcription and DNA synthesis, concerned with repeat duplication, recombination, branch resolution, or damage repair may also be involved with the genome maturation process. To gain insight into the biochemical activities needed for herpesvirus genome maturation, 2-bromo-5,6-dichloro-1-β-d-ribofuranosyl benzimidazole riboside (BDCRB) was used to allow the accumulation of human cytomegalovirus concatemeric DNA while the formation of new genomes was being blocked. Genome formation was restored upon BDCRB removal, and addition of various inhibitors during this time window permitted evaluation of their effects on genome maturation. Inhibitors of protein synthesis, RNA transcription, and the viral DNA polymerase only modestly reduced genome formation, demonstrating that these activities are not required for genome maturation. In contrast, drugs that inhibit both viral and host DNA polymerases potently blocked genome formation. Radioisotope incorporation in the presence of a viral DNA polymerase inhibitor further suggested that significant host-mediated DNA synthesis occurs throughout the viral genome. These results indicate a role for host DNA polymerases in genome maturation and are consistent with a need for terminal repeat duplication, debranching, or damage repair concomitant with DNA packaging or cleavage. Similarities to previously reported effects of BDCRB on guinea pig cytomegalovirus were also noted; however, BDCRB induced low-level formation of a supergenomic species called monomer+ DNA that is unique to human cytomegalovirus. Analysis of monomer+ DNA suggested a model for its formation in which BDCRB permits limited packaging of concatemeric DNA but induces skipping of cleavage sites.

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Tang, Ming, Huangqi Tang, Bo Tu, and Wei-Guo Zhu. "SIRT7: a sentinel of genome stability." Open Biology 11, no. 6 (June 2021): 210047. http://dx.doi.org/10.1098/rsob.210047.

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SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

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Ambrosio, Susanna, and Barbara Majello. "Autophagy Roles in Genome Maintenance." Cancers 12, no. 7 (July 4, 2020): 1793. http://dx.doi.org/10.3390/cancers12071793.

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In recent years, a considerable correlation has emerged between autophagy and genome integrity. A range of mechanisms appear to be involved where autophagy participates in preventing genomic instability, as well as in DNA damage response and cell fate decision. These initial findings have attracted particular attention in the context of malignancy; however, the crosstalk between autophagy and DNA damage response is just beginning to be explored and key questions remain that need to be addressed, to move this area of research forward and illuminate the overall consequence of targeting this process in human therapies. Here we present current knowledge on the complex crosstalk between autophagy and genome integrity and discuss its implications for cancer cell survival and response to therapy.

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Sengupta, Shiladitya, Haibo Wang, Chunying Yang, Bartosz Szczesny, Muralidhar L. Hegde, and Sankar Mitra. "Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription." Proceedings of the National Academy of Sciences 117, no. 36 (August 21, 2020): 22183–92. http://dx.doi.org/10.1073/pnas.1919445117.

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Among several reversible epigenetic changes occurring during transcriptional activation, only demethylation of histones and cytosine-phosphate-guanines (CpGs) in gene promoters and other regulatory regions by specific demethylase(s) generates reactive oxygen species (ROS), which oxidize DNA and other cellular components. Here, we show induction of oxidized bases and single-strand breaks (SSBs), but not direct double-strand breaks (DSBs), in the genome during gene activation by ligands of the nuclear receptor superfamily. We observed that these damages were preferentially repaired in promoters via the base excision repair (BER)/single-strand break repair (SSBR) pathway. Interestingly, BER/SSBR inhibition suppressed gene activation. Constitutive association of demethylases with BER/SSBR proteins in multiprotein complexes underscores the coordination of histone/DNA demethylation and genome repair during gene activation. However, ligand-independent transcriptional activation occurring during heat shock (HS) induction is associated with the generation of DSBs, the repair of which is likewise essential for the activation of HS-responsive genes. These observations suggest that the repair of distinct damages induced during diverse transcriptional activation is a universal prerequisite for transcription initiation. Because of limited investigation of demethylation-induced genome damage during transcription, this study suggests that the extent of oxidative genome damage resulting from various cellular processes is substantially underestimated.

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Sedwick, Caitlin. "Jiri Lukas: Visualizing genome integrity maintenance." Journal of Cell Biology 198, no. 1 (July 9, 2012): 4–5. http://dx.doi.org/10.1083/jcb.1981pi.

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Hazeslip, Lindsey, Maroof Khan Zafar, Muhammad Zain Chauhan, and Alicia K. Byrd. "Genome Maintenance by DNA Helicase B." Genes 11, no. 5 (May 21, 2020): 578. http://dx.doi.org/10.3390/genes11050578.

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DNA Helicase B (HELB) is a conserved helicase in higher eukaryotes with roles in the initiation of DNA replication and in the DNA damage and replication stress responses. HELB is a predominately nuclear protein in G1 phase where it is involved in initiation of DNA replication through interactions with DNA topoisomerase 2-binding protein 1 (TOPBP1), cell division control protein 45 (CDC45), and DNA polymerase α-primase. HELB also inhibits homologous recombination by reducing long-range end resection. After phosphorylation by cyclin-dependent kinase 2 (CDK2) at the G1 to S transition, HELB is predominately localized to the cytosol. However, this cytosolic localization in S phase is not exclusive. HELB has been reported to localize to chromatin in response to replication stress and to localize to the common fragile sites 16D (FRA16D) and 3B (FRA3B) and the rare fragile site XA (FRAXA) in S phase. In addition, HELB is phosphorylated in response to ionizing radiation and has been shown to localize to chromatin in response to various types of DNA damage, suggesting it has a role in the DNA damage response.

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Gamulin, Marija, Nevenka Kopjar, Mislav Grgić, Snježana Ramić, Vesna Bišof, and Vera Garaj-Vrhovac. "Genome Damage in Oropharyngeal Cancer Patients Treated by Radiotherapy." Croatian medical journal 49, no. 4 (August 2008): 515–27. http://dx.doi.org/10.3325/cmj.2008.4.515.

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Ermolaeva, Maria A., and Björn Schumacher. "Systemic DNA damage responses: organismal adaptations to genome instability." Trends in Genetics 30, no. 3 (March 2014): 95–102. http://dx.doi.org/10.1016/j.tig.2013.12.001.

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Nyberg, Kara A., Rhett J. Michelson, Charles W. Putnam, and Ted A. Weinert. "Toward Maintaining the Genome: DNA Damage and Replication Checkpoints." Annual Review of Genetics 36, no. 1 (December 2002): 617–56. http://dx.doi.org/10.1146/annurev.genet.36.060402.113540.

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Latif, Christine, Susan H. Harvey, and Susan J. O'Connell. "Ensuring the Stability of the Genome: DNA Damage Checkpoints." Scientific World JOURNAL 1 (2001): 684–702. http://dx.doi.org/10.1100/tsw.2001.297.

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The cellular response to DNA damage is vital for the cell�s ability to maintain genomic integrity. Checkpoint signalling pathways, which induce a cell cycle arrest in response to DNA damage, are an essential component of this process. This is reflected by the functional conservation of these pathways in all eukaryotes from yeast to mammalian cells. This review will examine the cellular response to DNA damage throughout the cell cycle. A key component of the DNA damage response is checkpoint signalling, which monitors the state of the genome prior to DNA replication (G1/S) and chromosome segregation (G2/M). Checkpoint signalling in model systems including mice, Xenopus laevis, Drosophila melanogaster, and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have been useful in elucidating these pathways in mammalian cells. An examination of this research, with emphasis on the function of checkpoint proteins, their relationship to DNA repair, and their involvement in oncogenesis is undertaken here.

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Zheng, Z., A. Cantor, and G. Bepler. "Global genome damage is predictive of cancer patients’ outcome." Journal of Clinical Oncology 23, no. 16_suppl (June 2005): 9542. http://dx.doi.org/10.1200/jco.2005.23.16_suppl.9542.

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Gamulin, Marija, Jelena Katić, Mirta Milić, Mislav Grgić, and Aleksandra Fučić. "Long-Term Follow-Up Study of Genome Damage Elimination in Patients with Testicular Seminoma Exposed to Ionising Radiation during Radiotherapy." Archives of Industrial Hygiene and Toxicology 62, no. 1 (March 1, 2011): 51–56. http://dx.doi.org/10.2478/10004-1254-62-2011-2089.

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Long-Term Follow-Up Study of Genome Damage Elimination in Patients with Testicular Seminoma Exposed to Ionising Radiation during RadiotherapyThe rate of genome damage elimination after therapeutic exposure to ionising radiation was estimated in stage I testicular seminoma patients monitored over a seven-year follow-up. DNA damage elimination in peripheral lymphocytes of ten subjects was analysed by the chromosome aberration assay. Seven years after the end of radiotherapy, significantly increased frequency of ring and dicentric chromosomes was still detected in comparison with baseline values. These results indicate the induction of genome instability. Long-term follow-up studies of cancer patients after radiotherapy could give us valuable information on the rate of genome damage elimination after exposure to ionising radiation and about the duration and manifestation of genome instability. This may be used in health risk assessment related to the possible development of secondary neoplasia. Studies such as this could have a great value both for oncology and radiation protection management protocols, especially after accidental overexposures.

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Wang, Haibo, and Muralidhar L. Hegde. "New Mechanisms of DNA Repair Defects in Fused in Sarcoma–Associated Neurodegeneration: Stage Set for DNA Repair-Based Therapeutics?" Journal of Experimental Neuroscience 13 (January 2019): 117906951985635. http://dx.doi.org/10.1177/1179069519856358.

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Genome damage and defective DNA repair are etiologically linked to several neurodegenerative disorders, including fused in sarcoma (FUS)–associated amyotrophic lateral sclerosis (ALS). However, the underlying mechanisms remain enigmatic, which is a roadblock for exploiting genome repair-targeted therapies. Our recent studies identified defects in DNA nick ligation and oxidative damage repair caused by mutations in the RNA/DNA-binding protein FUS in familial ALS patients. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. This is a critical step in the repair of oxidative genome damage, a foremost challenge for postmitotic neurons due to their high oxygen consumption. We discovered that mutant FUS significantly inhibited the recruitment of XRCC1/LigIII to DNA strand breaks, causing defects in DNA ligation during the repair of oxidative DNA damage, which contributed to neurodegeneration. While the FUS loss of function was responsible for the repair defects, increased oxidative genome damage due to mutant FUS aggregation could exacerbate the phenomenon. We highlight how these new molecular insights into previously undescribed DNA repair defect linked to FUS-associated neurodegeneration could provide an important opportunity for exploring DNA repair-based therapeutic avenues.

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Ho, Eric S., Catherine M. Newsom-Stewart, Lysa Diarra, and Caroline S. McCauley. "gb4gv: a genome browser forgeminivirus." PeerJ 5 (April 12, 2017): e3165. http://dx.doi.org/10.7717/peerj.3165.

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BackgroundGeminiviruses (familyGeminiviridae) are prevalent plant viruses that imperil agriculture globally, causing serious damage to the livelihood of farmers, particularly in developing countries. The virus evolves rapidly, attributing to its single-stranded genome propensity, resulting in worldwide circulation of diverse and viable genomes. Genomics is a prominent approach taken by researchers in elucidating the infectious mechanism of the virus. Currently, the NCBI Viral Genome website is a popular repository of viral genomes that conveniently provides researchers a centralized data source of genomic information. However, unlike the genome of living organisms, viral genomes most often maintain peculiar characteristics that fit into no single genome architecture. By imposing a unified annotation scheme on the myriad of viral genomes may downplay their hallmark features. For example, the viron of begomoviruses prevailing in America encapsulates two similar-sized circular DNA components and both are required for systemic infection of plants. However, the bipartite components are kept separately in NCBI as individual genomes with no explicit association in linking them. Thus, our goal is to build a comprehensiveGeminivirusgenomics database, namely gb4gv, that not only preserves genomic characteristics of the virus, but also supplements biologically relevant annotations that help to interrogate this virus, for example, the targeted host, putative iterons, siRNA targets, etc.MethodsWe have employed manual and automatic methods to curate 508 genomes from four major genera ofGeminiviridae, and 161 associated satellites obtained from NCBI RefSeq and PubMed databases.ResultsThese data are available for free access without registration from our website. Besides genomic content, our website provides visualization capability inherited from UCSC Genome Browser.DiscussionWith the genomic information readily accessible, we hope that our database will inspire researchers in gaining a better understanding of the incredible degree of diversity of these viruses, and of the complex relationships within and between the different genera in theGeminiviridae.Availability and ImplementationThe database can be found at:http://gb4gv.lafayette.edu.

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Zhu, Qiangyuan, Yichi Niu, Michael Gundry, and Chenghang Zong. "Single-cell damagenome profiling unveils vulnerable genes and functional pathways in human genome toward DNA damage." Science Advances 7, no. 27 (July 2021): eabf3329. http://dx.doi.org/10.1126/sciadv.abf3329.

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We report a novel single-cell whole-genome amplification method (LCS-WGA) that can efficiently capture spontaneous DNA damage existing in single cells. We refer to these damage-associated single-nucleotide variants as “damSNVs,” and the whole-genome distribution of damSNVs as the damagenome. We observed that in single human neurons, the damagenome distribution was significantly correlated with three-dimensional genome structures. This nonuniform distribution indicates different degrees of DNA damage effects on different genes. Next, we identified the functionals that were significantly enriched in the high-damage genes. Similar functionals were also enriched in the differentially expressed genes (DEGs) detected by single-cell transcriptome of both Alzheimer’s disease (AD) and autism spectrum disorder (ASD). This result can be explained by the significant enrichment of high-damage genes in the DEGs of neurons for both AD and ASD. The discovery of high-damage genes sheds new lights on the important roles of DNA damage in human diseases and disorders.

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Journal articles on the topic 'Genome damage'

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