Journal articles on the topic 'Zinc; genomic stability; DNA damage'
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Hosseinpour, Arash, Kamil Haliloglu, Kagan Tolga Cinisli, Guller Ozkan, Halil Ibrahim Ozturk, Alireza Pour-Aboughadareh, and Peter Poczai. "Application of Zinc Oxide Nanoparticles and Plant Growth Promoting Bacteria Reduces Genetic Impairment under Salt Stress in Tomato (Solanum lycopersicum L. ‘Linda’)." Agriculture 10, no. 11 (November 3, 2020): 521. http://dx.doi.org/10.3390/agriculture10110521.
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Salinity is an edaphic stress that dramatically restricts worldwide crop production. Nanomaterials and plant growth-promoting bacteria (PGPB) are currently used to alleviate the negative effects of various stresses on plant growth and development. This study investigates the protective effects of different levels of zinc oxide nanoparticles (ZnO-NPs) (0, 20, and 40 mg L−1) and PGPBs (no bacteria, Bacillus subtilis, Lactobacillus casei, Bacillus pumilus) on DNA damage and cytosine methylation changes in the tomato (Solanum lycopersicum L. ‘Linda’) seedlings under salinity stress (250 mM NaCl). Coupled Restriction Enzyme Digestion-Random Amplification (CRED-RA) and Randomly Amplified Polymorphic DNA (RAPD) approaches were used to analyze changes in cytosine methylation and to determine how genotoxic effects influence genomic stability. Salinity stress increased the polymorphism rate assessed by RAPD, while PGPB and ZnO-NPs reduced the adverse effects of salinity stress. Genomic template stability was increased by the PGPBs and ZnO-NPs application; this increase was significant when Lactobacillus casei and 40 mg L−1 of ZnO-NPs were used.A decreased level of DNA methylation was observed in all treatments. Taken together, the use of PGPB and ZnO-NPs had a general positive effect under salinity stress reducing genetic impairment in tomato seedlings.
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Abdel-Halim, Khaled Yassin, Safaa Ramadan Osman, Atef Mohamed Khedr Nassar, Alaa Khozimy, and Heba Mohamed El-Danasoury. "Use of DNA adduct and histopathological defects as indications for bio-persistence potency of zinc oxide nanoparticles in gastropod, Monacha cartusiana (Mǜller) after short-term exposure." Environmental Analysis Health and Toxicology 37, no. 3 (September 8, 2022): e2022025. http://dx.doi.org/10.5620/eaht.2022025.
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The cytotoxic effects of metallic nanoparticles (MNPs) might be revealed in genomic and histopathological defects. Therefore current study aimed to assess the bio-persistence and adverse effects potency of zinc oxide nanoparticles (ZnONPs) in the gastropod, Monacha cartusiana. Gastropods were exposed to 74 μg/mL for 14 d then the DNA adduct and histopathological defect profiles were assessed. The results demonstrated significant decline in the estimated genomic template stability (GTS%) in haemolymph and digestive gland ranging from 10.0 to 42.9% in treated animals compared to controls. In the treated and recovered snails, randomly amplified polymorphic (RAPD)-DNA showed the appearance and/or disappearance of DNA bands, indicating DNA damage due to the cytotoxicity of ZnONPs on gastropods. Significant defects in microvilli (MV), nucleus (N), mitochondria (M), and execratory glands (EXG) were noticed in the treated individuals with respect to controls. The remaining live animals were subjected to a recovery period (14 d, without treatment) and slight recovery profiles were reported for both measures compared to the control group. The recovery pattern was recognized in the nucleus/cytoplasm ratio with 0.186 and 0.428 in the treated and recovered groups concerning their control (0.176). The studied parameters reported herein might be reliable tools to assess accumulation and bio-persistence patterns of NPs in the organisms for short-term exposure indicating the cytotoxic and genotoxic effects. Also, gastropods may provide simple models for evaluating the ecotoxicological effects of nanomaterials.
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Johnson, R. E., S. T. Henderson, T. D. Petes, S. Prakash, M. Bankmann, and L. Prakash. "Saccharomyces cerevisiae RAD5-encoded DNA repair protein contains DNA helicase and zinc-binding sequence motifs and affects the stability of simple repetitive sequences in the genome." Molecular and Cellular Biology 12, no. 9 (September 1992): 3807–18. http://dx.doi.org/10.1128/mcb.12.9.3807-3818.1992.
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rad5 (rev2) mutants of Saccharomyces cerevisiae are sensitive to UV light and other DNA-damaging agents, and RAD5 is in the RAD6 epistasis group of DNA repair genes. To unambiguously define the function of RAD5, we have cloned the RAD5 gene, determined the effects of the rad5 deletion mutation on DNA repair, DNA damage-induced mutagenesis, and other cellular processes, and analyzed the sequence of RAD5-encoded protein. Our genetic studies indicate that RAD5 functions primarily with RAD18 in error-free postreplication repair. We also show that RAD5 affects the rate of instability of poly(GT) repeat sequences. Genomic poly(GT) sequences normally change length at a rate of about 10(-4); this rate is approximately 10-fold lower in the rad5 deletion mutant than in the corresponding isogenic wild-type strain. RAD5 encodes a protein of 1,169 amino acids of M(r) 134,000, and it contains several interesting sequence motifs. All seven conserved domains found associated with DNA helicases are present in RAD5. RAD5 also contains a cysteine-rich sequence motif that resembles the corresponding sequences found in 11 other proteins, including those encoded by the DNA repair gene RAD18 and the RAG1 gene required for immunoglobin gene arrangement. A leucine zipper motif preceded by a basic region is also present in RAD5. The cysteine-rich region may coordinate the binding of zinc; this region and the basic segment might constitute distinct DNA-binding domains in RAD5. Possible roles of RAD5 putative ATPase/DNA helicase activity in DNA repair and in the maintenance of wild-type rates of instability of simple repetitive sequences are discussed.
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Johnson, R. E., S. T. Henderson, T. D. Petes, S. Prakash, M. Bankmann, and L. Prakash. "Saccharomyces cerevisiae RAD5-encoded DNA repair protein contains DNA helicase and zinc-binding sequence motifs and affects the stability of simple repetitive sequences in the genome." Molecular and Cellular Biology 12, no. 9 (September 1992): 3807–18. http://dx.doi.org/10.1128/mcb.12.9.3807.
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rad5 (rev2) mutants of Saccharomyces cerevisiae are sensitive to UV light and other DNA-damaging agents, and RAD5 is in the RAD6 epistasis group of DNA repair genes. To unambiguously define the function of RAD5, we have cloned the RAD5 gene, determined the effects of the rad5 deletion mutation on DNA repair, DNA damage-induced mutagenesis, and other cellular processes, and analyzed the sequence of RAD5-encoded protein. Our genetic studies indicate that RAD5 functions primarily with RAD18 in error-free postreplication repair. We also show that RAD5 affects the rate of instability of poly(GT) repeat sequences. Genomic poly(GT) sequences normally change length at a rate of about 10(-4); this rate is approximately 10-fold lower in the rad5 deletion mutant than in the corresponding isogenic wild-type strain. RAD5 encodes a protein of 1,169 amino acids of M(r) 134,000, and it contains several interesting sequence motifs. All seven conserved domains found associated with DNA helicases are present in RAD5. RAD5 also contains a cysteine-rich sequence motif that resembles the corresponding sequences found in 11 other proteins, including those encoded by the DNA repair gene RAD18 and the RAG1 gene required for immunoglobin gene arrangement. A leucine zipper motif preceded by a basic region is also present in RAD5. The cysteine-rich region may coordinate the binding of zinc; this region and the basic segment might constitute distinct DNA-binding domains in RAD5. Possible roles of RAD5 putative ATPase/DNA helicase activity in DNA repair and in the maintenance of wild-type rates of instability of simple repetitive sequences are discussed.
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Srivastav, Anurag Kumar, Akhilesh Kumar, Jyoti Prakash, Dhirendra Singh, Pankaj Jagdale, Jai Shankar, and Mahadeo Kumar. "Genotoxicity evaluation of zinc oxide nanoparticles in Swiss mice after oral administration using chromosomal aberration, micronuclei, semen analysis, and RAPD profile." Toxicology and Industrial Health 33, no. 11 (September 26, 2017): 821–34. http://dx.doi.org/10.1177/0748233717717842.
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The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanotechnology. Thus, rising production of nanoparticles (NPs) increases the possible risks to the environment and occupationally exposed humans. Hence, it is indispensable to appraise the safety toxicity including genotoxicity for these NPs. In the present study, we have evaluated the genotoxic effect of ZnO NPs after oral administration to Swiss mice at dose levels of 300 and 2000 mg/kg body weight. These doses were administered for 2 days at 24 h apart. Chromosomal aberration (CA) and micronucleus tests were conducted following Organization for Economic Co-operation and Development guidelines. DNA damage was evaluated at 0, 24, 48, and 72 h posttreatment using a randomly amplified polymorphic DNA (RAPD) assay; additionally, semen analyses were also performed at 34.5 days post oral exposure. The reactive oxygen species (ROS), 8-oxo-2′-deoxyguanosine and CAs were increased ( p < 0.05) at the highest dosage (2000 mg/kg) of ZnO NPs compared to controls. Aberrant sperm morphology with reduced sperm count and motility were also present ( p < 0.05) in the high-dose group. Based on the RAPD assay, the genomic template stability within the high-dose group (<90%) was less than the controls (100%). The results suggested that ZnO NPs are mildly genotoxic in a dose-related manner and this toxicity were induced by generation of ROS.
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Lee, Su-jin, Han Byeol Oh, and Sung-il Yoon. "Crystal Structure of the Recombination Mediator Protein RecO from Campylobacter jejuni and Its Interaction with DNA and a Zinc Ion." International Journal of Molecular Sciences 23, no. 17 (August 26, 2022): 9667. http://dx.doi.org/10.3390/ijms23179667.
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Homologous recombination is involved in repairing DNA damage, contributing to maintaining the integrity and stability of viral and cellular genomes. In bacteria, the recombination mediator proteins RecO and RecR are required to load the RecA recombinase on ssDNA for homologous recombination. To structurally and functionally characterize RecO, we determined the crystal structure of RecO from Campylobacter jejuni (cjRecO) at a 1.8 Å resolution and biochemically assessed its capacity to interact with DNA and a metal ion. cjRecO folds into a curved rod-like structure that consists of an N-terminal domain (NTD), C-terminal domain (CTD), and Zn2+-binding domain (ZnD). The ZnD at the end of the rod-like structure coordinates three cysteine residues and one histidine residue to accommodate a Zn2+ ion. Based on an extensive comparative analysis of RecO structures and sequences, we propose that the Zn2+-binding consensus sequence of RecO is CxxC…C/HxxC/H/D. The interaction with Zn2+ is indispensable for the protein stability of cjRecO but does not seem to be required for the recombination mediator function. cjRecO also interacts with ssDNA as part of its biological function, potentially using the positively charged patch in the NTD and CTD. However, cjRecO displays a low ssDNA-binding affinity, suggesting that cjRecO requires RecR to efficiently recognize ssDNA for homologous recombination.
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Voisset, Edwige, Eva Moravcsik, Eva W. Stratford, Amie Jaye, Christopher J. Palgrave, Robert K. Hills, Paolo Salomoni, Scott C. Kogan, Ellen Solomon, and David Grimwade. "Pml Nuclear Body Disruption Cooperates in APL Pathogenesis, Impacting DNA Damage Repair Pathways." Blood 128, no. 22 (December 2, 2016): 742. http://dx.doi.org/10.1182/blood.v128.22.742.742.
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Abstract Acute promyelocytic leukemia (APL) is driven by the oncogene PML-RARA which is generated by fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes, and which strongly interferes with downstream signalling and the architecture of multiprotein structures known as PML nuclear bodies (NBs). NB disruption is a diagnostic hallmark of APL, yet the significance of this phenomenon to disease pathogenesis and treatment response remains poorly understood. The majority of APL patients can now be cured with combination therapy with arsenic trioxide (ATO) and ATRA (All Trans-Retinoic Acid), which synergize promoting re-formation of disrupted Pml NBs. To date, the importance of NB disruption has only been studied in vitro. To address this, we generated a knock-in mouse model with targeted NB disruption achieved through mutation of key zinc-binding cysteine residues (C62A/C65A) in the RING domain of Pml. Homozygous PmlC62A/C65A mice are viable, and developmentally normal. At a cellular level, Pml NB disruption was confirmed and treatment with ATO was associated with defective Pml SUMOylation and degradation. A key feature of APL fusion proteins is the capacity to homodimerise (mediated by the fusion partner e.g. PML), which is not a feature of wild-type RARα. This forced homodimerisation of RARα has been shown to be critical for APL pathogenesis. We investigated whether Pml NB disruption could cooperate in vivo with forced RARα homodimerisation (mediated artificially by linking RARα to the dimerisation domain of the NFκB p50 subunit). While no leukemias arose in PmlC62A/C65A mice, p50-RARα mice expressing PmlC62A/C65A presented a doubling in the rate of leukemia development (p<0.0001) compared to PmlWT-p50-RARα, leading to a penetrance comparable to that observed in previously published PML-RARα transgenic models. Moreover, the latency period to onset of leukemia was significantly reduced in the context of NB disruption (p=0.008). ATRA treatment significantly improved the survival of mice transplanted with PmlWT-p50-RARα or Pml-RARα leukemic blasts, but not with PmlC62A/C65A-p50-RARα. These data reveal not only the key role of PML-RARα expression-induced NB disruption in APL development, but also the importance of re-formation of NBs for an effective response to differentiating drug. While formation of the PML-RARA fusion is considered an initiating event in APL pathogenesis, it is insufficient for the full leukemic phenotype. Exome sequencing studies have consistently identified presence of cooperating mutations. Since Pml and Pml NB have established roles in DNA repair and in the maintenance of genomic stability, we speculated that loss of NB integrity could affect these functions. Whole exome sequencing revealed a pattern of higher genomic instability in PmlC62A/C65A-p50-RARα leukemia as compared to PmlWT-p50-RARα, with detection of mutations found in human APL, including Kras, Ptpn11 and Usp9y. Using DNA repair reporter assays, we demonstrated that DNA repair via both non-homologous end joining (NHEJ; p=0.01) and homologous recombination (HR; p=0.006) pathways was less efficient in PmlC62A/C65A primary cells than in PmlWT cells. Importantly, using a PML-RARα-inducible cell line, comparable defects in the NHEJ and HR pathways, which were PML-RARα dependent, were identified. These data were also supported by an increase in sister-chromatid exchange (p<0.0001) and chromosome abnormality (p=0.0002) in the context of PmlC62A/C65A versus PmlWT. Interestingly, the kinetic of repair of ionising radiation (IR)-induced DNA double-strand breaks, assessed by analysis of γH2AX foci formation and clearance, was not affected. None of the DNA repair players analysed (e.g. Blm, Rad51 and 53BP1) failed to form foci in response to IR. However, their basal levels of foci were significantly greater in the presence of PmlC62A/C65A (p<0.04; quantified using Amnis ImageStreamX Mk II imaging flow cytometer). Additionally, we found that Rad51 foci showed a defect in localisation post-IR when PmlC62A/C65A was expressed, with impairment of Rad51 co-localisation and interaction with γH2AX. Altogether, our data therefore highlight the significant contribution of Pml NB to the effectiveness of DNA damage repair processes, and the manner in which their disruption mediated by the PML-RARα oncoprotein can assist APL pathogenesis. Disclosures Hills: TEVA: Honoraria. Grimwade:TEVA: Research Funding.
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Ishikawa, Kazuhiro, Hideshi Ishii, and Toshiyuki Saito. "DNA Damage-Dependent Cell Cycle Checkpoints and Genomic Stability." DNA and Cell Biology 25, no. 7 (July 2006): 406–11. http://dx.doi.org/10.1089/dna.2006.25.406.
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Zong, Chunyan, Tianyu Zhu, Jie He, Rui Huang, Renbing Jia, and Jianfeng Shen. "PARP mediated DNA damage response, genomic stability and immune responses." International Journal of Cancer 150, no. 11 (January 12, 2022): 1745–59. http://dx.doi.org/10.1002/ijc.33918.
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Lavin, Martin F., Geoff Birrell, Philip Chen, Sergei Kozlov, Shaun Scott, and Nuri Gueven. "ATM signaling and genomic stability in response to DNA damage." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 569, no. 1-2 (January 2005): 123–32. http://dx.doi.org/10.1016/j.mrfmmm.2004.04.020.
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Numata, Akihiko, Hui Si Kwok, Qi-Ling Zhou, Jia Li, Rebecca Hannah, Jihye Park, Vladimir Espinosa Angarcia, et al. "The Lysine Acetyltransferase Tip60 Is Required for Hematopoietic Stem Cell Maintenance." Blood 132, Supplement 1 (November 29, 2018): 2554. http://dx.doi.org/10.1182/blood-2018-99-118316.
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Abstract Hematopoietic stem cells (HSCs) are maintained for their two defining properties, a self-renewal and a multi-lineage differentiation ability, under various epigenetic processes. One of the epigenetic processes essential for HSC is a lysine acetylation, which was demonstrated in several previous studies utilizing knockout mice of a gene encoding a lysine acetyltransferase (KAT), such as Cbp/p300, Moz, or Mof. The lysine acetyl transferase 5, Kat5 (also called Tip60), is a member of MYST KAT family, defined by a protein containing a C2HC-type zinc finger and an acetyl-CoA binding domain, consisting of five members: Tip60, Moz, Morf, Hbo1, and Mof. Tip60 regulates gene transcription, genome stability, cell growth and apoptosis and has been demonstrated to be essential for embryonic development. To assess the role of Tip60 in murine HSC, we generated Tip60 conditional knockout mice in two different Cre strains (Mx1-Cre and Vav-iCre), wherein Tip60 gene was successfully deleted in HSCs. Tip60 abrogation induced embryonic and adult lethality due to hematopoietic failure. Remarkably, HSCs were rapidly depleted upon Tip60 disruption, exhibiting robust apoptosis, aberrant cell cycle progression, and accumulated DNA damages. Tip60Δ/Δ fetal LSK cells transduced with retroviruses expressing wild-type Tip60 recovered a long-term hematopoiesis in transplantation experiments, whereas acetyl transferase defective Tip60 did not rescue the reconstitution to any detectable level, suggesting that the Tip60 acetyltransferase activity is essential for HSC function. Gene set enrichment analysis in RNA-seq demonstrated that Tip60 was significantly associated with genes involved in cell-cycle and DNA repair process, and Myc transcriptional factors target gene sets. A genome-wide chromatin profiling corroborated these findings, uncovering a strong similarity between Tip60 and c-Myc binding genomic regions. Considering similarities of HSC phenotype between our Tip60 conditional knockout mice and c-myc and N-myc double knockout mice (Laurenti, E. et al., Cell Stem Cell 2008), Tip60 maintains HSC by regulating Myc target genes. We next evaluated alteration in histone modifications evoked by Tip60 deletion, performing ChIP-seq analysis in Tip60f/f; Rosa26-CreERT2 and Tip60f/f fetal c-Kit+ cells that were treated with 4-OHT. Intriguingly, we found that acetylated H2A.Z was enriched at the Tip60-bound active chromatin and Tip60 deletion reduced the acetylation level of H2A.Z at Myc target genes promoters, whereas neither H3K27 acetylation level, active promoter / enhancer mark, nor H3K27 tri-methylation level, repressive mark, were altered. Collectively, our results demonstrate that Tip60 - H2A.Z could be an epigenetic axis critical for active transcription of Myc target genes to maintain murine HSC. Disclosures No relevant conflicts of interest to declare.
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Srinivasan, Rajini, Nataliya Nady, Neha Arora, Laura J. Hsieh, Tomek Swigut, Geeta J. Narlikar, Mark Wossidlo, and Joanna Wysocka. "Zscan4 binds nucleosomal microsatellite DNA and protects mouse two-cell embryos from DNA damage." Science Advances 6, no. 12 (March 2020): eaaz9115. http://dx.doi.org/10.1126/sciadv.aaz9115.
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Zinc finger protein Zscan4 is selectively expressed in mouse two-cell (2C) embryos undergoing zygotic genome activation (ZGA) and in a rare subpopulation of embryonic stem cells with 2C-like features. Here, we show that Zscan4 specifically recognizes a subset of (CA)n microsatellites, repeat sequences prone to genomic instability. Zscan4-associated microsatellite regions are characterized by low nuclease sensitivity and high histone occupancy. In vitro, Zscan4 binds nucleosomes and protects them from disassembly upon torsional strain. Furthermore, Zscan4 depletion leads to elevated DNA damage in 2C mouse embryos in a transcription-dependent manner. Together, our results identify Zscan4 as a DNA sequence–dependent microsatellite binding factor and suggest a developmentally regulated mechanism, which protects fragile genomic regions from DNA damage at a time of embryogenesis associated with high transcriptional burden and genomic stress.
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Alhmoud, Jehad F., John F. Woolley, Ala-Eddin Al Moustafa, and Mohammed Imad Malki. "DNA Damage/Repair Management in Cancers." Cancers 12, no. 4 (April 23, 2020): 1050. http://dx.doi.org/10.3390/cancers12041050.
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DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways.
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Hopkins, Jessica L., Li Lan, and Lee Zou. "DNA repair defects in cancer and therapeutic opportunities." Genes & Development 36, no. 5-6 (March 1, 2022): 278–93. http://dx.doi.org/10.1101/gad.349431.122.
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DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.
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Torres, Michael J., Raj K. Pandita, Ozlem Kulak, Rakesh Kumar, Etienne Formstecher, Nobuo Horikoshi, Kalpana Mujoo, et al. "Role of the Exocyst Complex Component Sec6/8 in Genomic Stability." Molecular and Cellular Biology 35, no. 21 (August 17, 2015): 3633–45. http://dx.doi.org/10.1128/mcb.00768-15.
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The exocyst is a heterooctomeric complex well appreciated for its role in the dynamic assembly of specialized membrane domains. Accumulating evidence indicates that this macromolecular machine also serves as a physical platform that coordinates regulatory cascades supporting biological systems such as host defense signaling, cell fate, and energy homeostasis. The isolation of multiple components of the DNA damage response (DDR) as exocyst-interacting proteins, together with the identification of Sec8 as a suppressor of the p53 response, suggested functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in resistance to ionizing radiation (IR) and accelerated resolution of DNA damage. This occurred at the expense of genomic integrity, as enhanced recombination frequencies correlated with the accumulation of aberrant chromatid exchanges. Sec8 perturbation resulted in the accumulation of ATF2 and RNF20 and the promiscuous accumulation of DDR-associated chromatin marks and Rad51 repairosomes. Thus, the exocyst supports DNA repair fidelity by limiting the formation of repair chromatin in the absence of DNA damage.
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Chen, Andy Chun Hang, Qian Peng, Sze Wan Fong, Kai Chuen Lee, William Shu Biu Yeung, and Yin Lau Lee. "DNA Damage Response and Cell Cycle Regulation in Pluripotent Stem Cells." Genes 12, no. 10 (September 29, 2021): 1548. http://dx.doi.org/10.3390/genes12101548.
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Pluripotent stem cells (PSCs) hold great promise in cell-based therapy because of their pluripotent property and the ability to proliferate indefinitely. Embryonic stem cells (ESCs) derived from inner cell mass (ICM) possess unique cell cycle control with shortened G1 phase. In addition, ESCs have high expression of homologous recombination (HR)-related proteins, which repair double-strand breaks (DSBs) through HR or the non-homologous end joining (NHEJ) pathway. On the other hand, the generation of induced pluripotent stem cells (iPSCs) by forced expression of transcription factors (Oct4, Sox2, Klf4, c-Myc) is accompanied by oxidative stress and DNA damage. The DNA repair mechanism of DSBs is therefore critical in determining the genomic stability and efficiency of iPSCs generation. Maintaining genomic stability in PSCs plays a pivotal role in the proliferation and pluripotency of PSCs. In terms of therapeutic application, genomic stability is the key to reducing the risks of cancer development due to abnormal cell replication. Over the years, we and other groups have identified important regulators of DNA damage response in PSCs, including FOXM1, SIRT1 and PUMA. They function through transcription regulation of downstream targets (P53, CDK1) that are involved in cell cycle regulations. Here, we review the fundamental links between the PSC-specific HR process and DNA damage response, with a focus on the roles of FOXM1 and SIRT1 on maintaining genomic integrity.
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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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Archambeau, Jérôme, Alice Blondel, and Rémy Pedeux. "Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation." Cancers 12, no. 1 (December 24, 2019): 58. http://dx.doi.org/10.3390/cancers12010058.
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The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.
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Zhu, Guangrong, Xiangyang Zheng, Zhifeng Wang, and Xingzhi Xu. "Post-Translational Modifications by Lipid Metabolites during the DNA Damage Response and Their Role in Cancer." Biomolecules 12, no. 11 (November 8, 2022): 1655. http://dx.doi.org/10.3390/biom12111655.
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Genomic DNA damage occurs as an inevitable consequence of exposure to harmful exogenous and endogenous agents. Therefore, the effective sensing and repair of DNA damage are essential for maintaining genomic stability and cellular homeostasis. Inappropriate responses to DNA damage can lead to genomic instability and, ultimately, cancer. Protein post-translational modifications (PTMs) are a key regulator of the DNA damage response (DDR), and recent progress in mass spectrometry analysis methods has revealed that a wide range of metabolites can serve as donors for PTMs. In this review, we will summarize how the DDR is regulated by lipid metabolite-associated PTMs, including acetylation, S-succinylation, N-myristoylation, palmitoylation, and crotonylation, and the implications for tumorigenesis. We will also discuss potential novel targets for anti-cancer drug development.
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Ovejero, Sara, Avelino Bueno, and María P. Sacristán. "Working on Genomic Stability: From the S-Phase to Mitosis." Genes 11, no. 2 (February 20, 2020): 225. http://dx.doi.org/10.3390/genes11020225.
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Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of genomic instability exist: DNA damage, replicative stress, and chromosome segregation defects. In response to these challenges, eukaryotic cells have evolved control mechanisms, also known as checkpoint systems, which sense under-replicated or damaged DNA and activate specialized DNA repair machineries. Cells make use of these checkpoints throughout interphase to shield genome integrity before mitosis. Later on, when the cells enter into mitosis, the spindle assembly checkpoint (SAC) is activated and remains active until the chromosomes are properly attached to the spindle apparatus to ensure an equal segregation among daughter cells. All of these processes are tightly interconnected and under strict regulation in the context of the cell division cycle. The chromosomal instability underlying cancer pathogenesis has recently emerged as a major source for understanding the mitotic processes that helps to safeguard genome integrity. Here, we review the special interconnection between the S-phase and mitosis in the presence of under-replicated DNA regions. Furthermore, we discuss what is known about the DNA damage response activated in mitosis that preserves chromosomal integrity.
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Cargill, Michael, Rasika Venkataraman, and Stanley Lee. "DEAD-Box RNA Helicases and Genome Stability." Genes 12, no. 10 (September 23, 2021): 1471. http://dx.doi.org/10.3390/genes12101471.
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DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between genomic stability and several DEAD-box RNA helicase family proteins including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, and DDX41. For each helicase, we have reviewed evidence supporting their role in protecting the genome and their suggested mechanisms. Such helicases regulate the expression of factors promoting genomic stability, prevent DNA damage, and can participate directly in the response and repair of DNA damage. Finally, we summarized the pathological and therapeutic relationship between DEAD-box RNA helicases and cancer with respect to their novel role in genome stability.
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Mitxelena, Jone, Aintzane Apraiz, Jon Vallejo-Rodríguez, Iraia García-Santisteban, Asier Fullaondo, Mónica Alvarez-Fernández, Marcos Malumbres, and Ana M. Zubiaga. "An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability." Nucleic Acids Research 46, no. 9 (March 24, 2018): 4546–59. http://dx.doi.org/10.1093/nar/gky218.
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Abstract The cellular response to DNA damage is essential for maintaining the integrity of the genome. Recent evidence has identified E2F7 as a key player in DNA damage-dependent transcriptional regulation of cell-cycle genes. However, the contribution of E2F7 to cellular responses upon genotoxic damage is still poorly defined. Here we show that E2F7 represses the expression of genes involved in the maintenance of genomic stability, both throughout the cell cycle and upon induction of DNA lesions that interfere with replication fork progression. Knockdown of E2F7 leads to a reduction in 53BP1 and FANCD2 foci and to fewer chromosomal aberrations following treatment with agents that cause interstrand crosslink (ICL) lesions but not upon ionizing radiation. Accordingly, E2F7-depleted cells exhibit enhanced cell-cycle re-entry and clonogenic survival after exposure to ICL-inducing agents. We further report that expression and functional activity of E2F7 are p53-independent in this context. Using a cell-based assay, we show that E2F7 restricts homologous recombination through the transcriptional repression of RAD51. Finally, we present evidence that downregulation of E2F7 confers an increased resistance to chemotherapy in recombination-deficient cells. Taken together, our results reveal an E2F7-dependent transcriptional program that contributes to the regulation of DNA repair and genomic integrity.
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Mitxelena, Jone, Aintzane Apraiz, Jon Vallejo-Rodríguez, Iraia García-Santisteban, Asier Fullaondo, Mónica Alvarez-Fernández, Marcos Malumbres, and Ana M. Zubiaga. "An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability." Nucleic Acids Research 47, no. 14 (July 3, 2019): 7716–17. http://dx.doi.org/10.1093/nar/gkz587.
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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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Lenzken, Silvia C., Alessia Loffreda, and Silvia M. L. Barabino. "RNA Splicing: A New Player in the DNA Damage Response." International Journal of Cell Biology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/153634.
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It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors.
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Bradbury, J. M., and S. P. Jackson. "The complex matter of DNA double-strand break detection." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 40–44. http://dx.doi.org/10.1042/bst0310040.
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To maintain genomic stability, despite constant exposure to agents that damage DNA, eukaryotic cells have developed elaborate and highly conserved pathways of DNA damage sensing, signalling and repair. In this review, we concentrate mainly on what we know about DNA damage sensing with particular reference to Lcd1p, a yeast protein that functions early in DNA damage signalling, and MDC1 (mediator of DNA damage checkpoint 1), a recently identified human protein that may be involved in recruiting the MRE11 complex to radiation-induced nuclear foci. We describe a model for the DNA damage response in which factors are recruited sequentially to sites of DNA damage to form complexes that can amplify the original signal and propagate it to the multitude of response pathways necessary for genome stability.
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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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Kokkalis, Antonis, Praveen Anand, Monica S. Nair, Johannes M. Waldschmidt, Julia Frede, Tushara Vijaykumar, Amy Guillaumet-Adkins, Valeriya Dimitrova, Birgit Knoechel, and Jens G. Lohr. "Chromatin Structure Dynamics Preserve Genome Stability in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 1777. http://dx.doi.org/10.1182/blood-2019-127495.
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Introduction: Multiple myeloma (MM) is a genetically complex disease with extensive clonal heterogeneity. Substantial genomic instability in MM is illustrated by extensive copy number variations (CNVs) that can be detected in almost every MM patient. The molecular basis of this genomic instability in MM is not clear. Linker histones are dynamic components of chromatin and mutations in these molecules are present in ~6% of MM patients. Two of the linker histone super-family, HIST1H1Eand HIST1H1Care the most frequently mutated members of the family in MM and their mutations mostly occur in a clonal fashion. Interestingly, it has been reported in human cell lines and in other species that linker histone loss affects DNA damage/repair pathways and leads to transcription-replication conflicts. Based on these data we hypothesized that mutation or genomic loss of linker histones affects the genome stability of MM cells. To test this hypothesis, we developed an experimental system using CRISPR/Cas9 genome editing to generate MM linker histone-deficient cells. Low-pass whole genome sequencing (LPWGS), immunoblotting and immunofluorescent experiments were performed for genomic, molecular and functional characterization. We found that HIST1H1E,HIST1H1Cand H1FXwere the most abundantly expressed members of the linker histone family in primary myeloma cells and that myeloma cells have the highest dependency on HIST1H1Eand HIST1H1Cwhen compared to all other cancer cell lines derived from other tissues. We used OPM2 and U266 myeloma cell lines and generated knock-out variants of HIST1H1E, HIST1H1Cand H1FXlinker histones by inserting a biallelic stop codon, followed by generation of individual single-cell clones that were used as replicates. We first asked if linker histone deficient cells preserve genome stability. To address this question, we performed low pass whole genome sequencing and found more copy number abnormalities in linker histone deficient myeloma cells, when compared to wild-type cells. Moreover, linker histone deficient cells showed increased DNA damage as indicated by higher frequency of nuclear foci that were positive for damage dependent phosphorylation of the histone variant H2AX ( γH2AX). This was associated with an increased frequency of micronuclei in linker histones deficient cells, suggesting defects in mitotic fidelity and in genome stability. These micronuclei were positive for γH2AX by microscopic staining, indicative of DNA damage. We then asked if the DNA damage in micronuclei is due to defective and asynchronous DNA replication when the myeloma cells are exposed to etoposide, a topoisomerase inhibitor that induces DNA replication stress and double-strand DNA breaks (DSBs). Etoposide treatment of myeloma cells caused DNA replication stress, as measured by immunofluorescent staining of micronuclei for Replication Protein A (RPA). Conclusions: Our results demonstrate that loss of linker histones is associated with increased copy number abnormalities, extensive DNA damage and increased frequency of micronuclei, most likely as a consequence of replication stress. These data provide a potential mechanism of how chromatin structure dynamics preserve genome stability in myeloma cells. Disclosures Lohr: Celgene: Research Funding; T2 Biosystems: Honoraria.
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Lu, Ruiqing, Han Zhang, Yi-Nan Jiang, Zhao-Qi Wang, Litao Sun, and Zhong-Wei Zhou. "Post-Translational Modification of MRE11: Its Implication in DDR and Diseases." Genes 12, no. 8 (July 28, 2021): 1158. http://dx.doi.org/10.3390/genes12081158.
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Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their association with diseases such as cancer.
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Jones, Rebecca M., and Eva Petermann. "Replication fork dynamics and the DNA damage response." Biochemical Journal 443, no. 1 (March 14, 2012): 13–26. http://dx.doi.org/10.1042/bj20112100.
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Prevention and repair of DNA damage is essential for maintenance of genomic stability and cell survival. DNA replication during S-phase can be a source of DNA damage if endogenous or exogenous stresses impair the progression of replication forks. It has become increasingly clear that DNA-damage-response pathways do not only respond to the presence of damaged DNA, but also modulate DNA replication dynamics to prevent DNA damage formation during S-phase. Such observations may help explain the developmental defects or cancer predisposition caused by mutations in DNA-damage-response genes. The present review focuses on molecular mechanisms by which DNA-damage-response pathways control and promote replication dynamics in vertebrate cells. In particular, DNA damage pathways contribute to proper replication by regulating replication initiation, stabilizing transiently stalled forks, promoting replication restart and facilitating fork movement on difficult-to-replicate templates. If replication fork progression fails to be rescued, this may lead to DNA damage and genomic instability via nuclease processing of aberrant fork structures or incomplete sister chromatid separation during mitosis.
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Narbonne-Reveau, Karine, and Mary Lilly. "The Cyclin-dependent Kinase Inhibitor Dacapo Promotes Genomic Stability during Premeiotic S Phase." Molecular Biology of the Cell 20, no. 7 (April 2009): 1960–69. http://dx.doi.org/10.1091/mbc.e08-09-0916.
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The proper execution of premeiotic S phase is essential to both the maintenance of genomic integrity and accurate chromosome segregation during the meiotic divisions. However, the regulation of premeiotic S phase remains poorly defined in metazoa. Here, we identify the p21Cip1/p27Kip1/p57Kip2-like cyclin-dependent kinase inhibitor (CKI) Dacapo (Dap) as a key regulator of premeiotic S phase and genomic stability during Drosophila oogenesis. In dap−/− females, ovarian cysts enter the meiotic cycle with high levels of Cyclin E/cyclin-dependent kinase (Cdk)2 activity and accumulate DNA damage during the premeiotic S phase. High Cyclin E/Cdk2 activity inhibits the accumulation of the replication-licensing factor Doubleparked/Cdt1 (Dup/Cdt1). Accordingly, we find that dap−/− ovarian cysts have low levels of Dup/Cdt1. Moreover, mutations in dup/cdt1 dominantly enhance the dap−/− DNA damage phenotype. Importantly, the DNA damage observed in dap−/− ovarian cysts is independent of the DNA double-strands breaks that initiate meiotic recombination. Together, our data suggest that the CKI Dap promotes the licensing of DNA replication origins for the premeiotic S phase by restricting Cdk activity in the early meiotic cycle. Finally, we report that dap−/− ovarian cysts frequently undergo an extramitotic division before meiotic entry, indicating that Dap influences the timing of the mitotic/meiotic transition.
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Surjana, Devita, Gary M. Halliday, and Diona L. Damian. "Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair." Journal of Nucleic Acids 2010 (2010): 1–13. http://dx.doi.org/10.4061/2010/157591.
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Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerousin vitroandin vivostudies have clearly shown that PARP-1 and NAD+status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.
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Verma, Nagendra, Matteo Franchitto, Azzurra Zonfrilli, Samantha Cialfi, Rocco Palermo, and Claudio Talora. "DNA Damage Stress: Cui Prodest?" International Journal of Molecular Sciences 20, no. 5 (March 1, 2019): 1073. http://dx.doi.org/10.3390/ijms20051073.
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DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death.
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Fitieh, Amira, Andrew J. Locke, Mobina Motamedi, and Ismail Hassan Ismail. "The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability." International Journal of Molecular Sciences 22, no. 6 (March 15, 2021): 2976. http://dx.doi.org/10.3390/ijms22062976.
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The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.
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Friedberg, E. "DNA Repairâresponses to DNA damage and other aspects of genomic stability A new journal format." DNA Repair 1, no. 1 (January 22, 2002): 1–2. http://dx.doi.org/10.1016/s1568-7864(01)00002-7.
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Doherty, Rachel, and Srinivasan Madhusudan. "DNA Repair Endonucleases." Journal of Biomolecular Screening 20, no. 7 (April 15, 2015): 829–41. http://dx.doi.org/10.1177/1087057115581581.
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Genomic DNA is constantly exposed to endogenous and exogenous damaging agents. To overcome these damaging effects and maintain genomic stability, cells have robust coping mechanisms in place, including repair of the damaged DNA. There are a number of DNA repair pathways available to cells dependent on the type of damage induced. The removal of damaged DNA is essential to allow successful repair. Removal of DNA strands is achieved by nucleases. Exonucleases are those that progressively cut from DNA ends, and endonucleases make single incisions within strands of DNA. This review focuses on the group of endonucleases involved in DNA repair pathways, their mechanistic functions, roles in cancer development, and how targeting these enzymes is proving to be an exciting new strategy for personalized therapy in cancer.
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Scheijen, Elle E. M., and David M. Wilson. "Genome Integrity and Neurological Disease." International Journal of Molecular Sciences 23, no. 8 (April 8, 2022): 4142. http://dx.doi.org/10.3390/ijms23084142.
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Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and neurodegenerative disease. This idea is supported by the fact that individuals who harbor pathogenic mutations in DNA damage response genes experience profound neuropathological manifestations. The review article here provides a general overview of the nervous system, the threats to DNA stability, and the mechanisms that protect genomic integrity while highlighting the connections of DNA repair defects to neurological disease. The information presented should serve as a prelude to the Special Issue “Genome Stability and Neurological Disease”, where experts discuss the role of DNA repair in preserving central nervous system function in greater depth.
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Zhou, Qing, Kieu T. M. Pham, Huiqing Hu, Yasuhiro Kurasawa, and Ziyin Li. "A kinetochore-based ATM/ATR-independent DNA damage checkpoint maintains genomic integrity in trypanosomes." Nucleic Acids Research 47, no. 15 (May 31, 2019): 7973–88. http://dx.doi.org/10.1093/nar/gkz476.
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Abstract DNA damage-induced cell cycle checkpoints serve as surveillance mechanisms to maintain genomic stability, and are regulated by ATM/ATR-mediated signaling pathways that are conserved from yeast to humans. Trypanosoma brucei, an early divergent microbial eukaryote, lacks key components of the conventional DNA damage-induced G2/M cell cycle checkpoint and the spindle assembly checkpoint, and nothing is known about how T. brucei controls its cell cycle checkpoints. Here we discover a kinetochore-based, DNA damage-induced metaphase checkpoint in T. brucei. MMS-induced DNA damage triggers a metaphase arrest by modulating the abundance of the outer kinetochore protein KKIP5 in an Aurora B kinase- and kinetochore-dependent, but ATM/ATR-independent manner. Overexpression of KKIP5 arrests cells at metaphase through stabilizing the mitotic cyclin CYC6 and the cohesin subunit SCC1, mimicking DNA damage-induced metaphase arrest, whereas depletion of KKIP5 alleviates the DNA damage-induced metaphase arrest and causes chromosome mis-segregation and aneuploidy. These findings suggest that trypanosomes employ a novel DNA damage-induced metaphase checkpoint to maintain genomic integrity.
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Rey, Laurie, Julia M. Sidorova, Nadine Puget, François Boudsocq, Denis S. F. Biard, Raymond J. Monnat, Christophe Cazaux, and Jean-Sébastien Hoffmann. "Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication." Molecular and Cellular Biology 29, no. 12 (April 20, 2009): 3344–54. http://dx.doi.org/10.1128/mcb.00115-09.
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ABSTRACT Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting translesion DNA synthesis (TLS) past sunlight-induced cyclobutane pyrimidine dimers. Despite its well-established role in TLS synthesis, the role of Pol η in maintaining genome stability in the absence of external DNA damage has not been well explored. We show here that short hairpin RNA-mediated depletion of Pol η from undamaged human cells affects cell cycle progression and the rate of cell proliferation and results in increased spontaneous chromosome breaks and common fragile site expression with the activation of ATM-mediated DNA damage checkpoint signaling. These phenotypes were also observed in association with modified replication factory dynamics during S phase. In contrast to that seen in Pol η-depleted cells, none of these cellular or karyotypic defects were observed in cells depleted for Pol ι, the closest relative of Pol η. Our results identify a new role for Pol η in maintaining genomic stability during unperturbed S phase and challenge the idea that the sole functional role of Pol η in human cells is in TLS DNA damage tolerance and/or repair pathways following exogenous DNA damage.
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Klein, Hannah L. "Spontaneous Chromosome Loss in Saccharomyces cerevisiae Is Suppressed by DNA Damage Checkpoint Functions." Genetics 159, no. 4 (December 1, 2001): 1501–9. http://dx.doi.org/10.1093/genetics/159.4.1501.
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Abstract Genomic instability is one of the hallmarks of cancer cells and is often the causative factor in revealing recessive gene mutations that progress cells along the pathway to unregulated growth. Genomic instability can take many forms, including aneuploidy and changes in chromosome structure. Chromosome loss, loss and reduplication, and deletions are the majority events that result in loss of heterozygosity (LOH). Defective DNA replication, repair, and recombination can significantly increase the frequency of spontaneous genomic instability. Recently, DNA damage checkpoint functions that operate during the S-phase checkpoint have been shown to suppress spontaneous chromosome rearrangements in haploid yeast strains. To further study the role of DNA damage checkpoint functions in genomic stability, we have determined chromosome loss in DNA damage checkpoint-deficient yeast strains. We have found that the DNA damage checkpoints are essential for preserving the normal chromosome number and act synergistically with homologous recombination functions to ensure that chromosomes are segregated correctly to daughter cells. Failure of either of these processes increases LOH events. However, loss of the G2/M checkpoint does not result in an increase in chromosome loss, suggesting that it is the various S-phase DNA damage checkpoints that suppress chromosome loss. The mec1 checkpoint function mutant, defective in the yeast ATR homolog, results in increased recombination through a process that is distinct from that operative in wild-type cells.
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Bashkirov, Vladimir I., Jeff S. King, Elena V. Bashkirova, Jacqueline Schmuckli-Maurer, and Wolf-Dietrich Heyer. "DNA Repair Protein Rad55 Is a Terminal Substrate of the DNA Damage Checkpoints." Molecular and Cellular Biology 20, no. 12 (June 15, 2000): 4393–404. http://dx.doi.org/10.1128/mcb.20.12.4393-4404.2000.
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ABSTRACT Checkpoints, which are integral to the cellular response to DNA damage, coordinate transient cell cycle arrest and the induced expression of DNA repair genes after genotoxic stress. DNA repair ensures cellular survival and genomic stability, utilizing a multipathway network. Here we report evidence that the two systems, DNA damage checkpoint control and DNA repair, are directly connected by demonstrating that the Rad55 double-strand break repair protein of the recombinational repair pathway is a terminal substrate of DNA damage and replication block checkpoints. Rad55p was specifically phosphorylated in response to DNA damage induced by the alkylating agent methyl methanesulfonate, dependent on an active DNA damage checkpoint. Rad55p modification was also observed after gamma ray and UV radiation. The rapid time course of phosphorylation and the recombination defects identified in checkpoint-deficient cells are consistent with a role of the DNA damage checkpoint in activating recombinational repair. Rad55p phosphorylation possibly affects the balance between different competing DNA repair pathways.
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Kang, Josephine, and Martin J. Blaser. "UvrD Helicase Suppresses Recombination and DNA Damage-Induced Deletions." Journal of Bacteriology 188, no. 15 (August 1, 2006): 5450–59. http://dx.doi.org/10.1128/jb.00275-06.
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ABSTRACT UvrD, a highly conserved helicase involved in mismatch repair, nucleotide excision repair (NER), and recombinational repair, plays a critical role in maintaining genomic stability and facilitating DNA lesion repair in many prokaryotic species. In this report, we focus on the UvrD homolog in Helicobacter pylori, a genetically diverse organism that lacks many known DNA repair proteins, including those involved in mismatch repair and recombinational repair, and that is noted for high levels of inter- and intragenomic recombination and mutation. H. pylori contains numerous DNA repeats in its compact genome and inhabits an environment rich in DNA-damaging agents that can lead to increased rearrangements between such repeats. We find that H. pylori UvrD functions to repair DNA damage and limit homologous recombination and DNA damage-induced genomic rearrangements between DNA repeats. Our results suggest that UvrD and other NER pathway proteins play a prominent role in maintaining genome integrity, especially after DNA damage; thus, NER may be especially critical in organisms such as H. pylori that face high-level genotoxic stress in vivo.
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Ashour, Mohamed Elsaid, and Nima Mosammaparast. "Mechanisms of damage tolerance and repair during DNA replication." Nucleic Acids Research 49, no. 6 (March 8, 2021): 3033–47. http://dx.doi.org/10.1093/nar/gkab101.
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Abstract Accurate duplication of chromosomal DNA is essential for the transmission of genetic information. The DNA replication fork encounters template lesions, physical barriers, transcriptional machinery, and topological barriers that challenge the faithful completion of the replication process. The flexibility of replisomes coupled with tolerance and repair mechanisms counteract these replication fork obstacles. The cell possesses several universal mechanisms that may be activated in response to various replication fork impediments, but it has also evolved ways to counter specific obstacles. In this review, we will discuss these general and specific strategies to counteract different forms of replication associated damage to maintain genomic stability.
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Minchom, Anna, Caterina Aversa, and Juanita Lopez. "Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies." Therapeutic Advances in Medical Oncology 10 (January 1, 2018): 175883591878665. http://dx.doi.org/10.1177/1758835918786658.
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Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.
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Usman, Moonisah, Maria Woloshynowych, Jessica Carrilho Britto, Ivona Bilkevic, Bethany Glassar, Simon Chapman, Martha E. Ford-Adams, et al. "Obesity, oxidative DNA damage and vitamin D as predictors of genomic instability in children and adolescents." International Journal of Obesity 45, no. 9 (June 22, 2021): 2095–107. http://dx.doi.org/10.1038/s41366-021-00879-2.
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Abstract Background/objectives Epidemiological evidence indicates obesity in childhood and adolescence to be an independent risk factor for cancer and premature mortality in adulthood. Pathological implications from excess adiposity may begin early in life. Obesity is concurrent with a state of chronic inflammation, a well-known aetiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted attention for its anti-inflammatory properties and role in genomic integrity and stability. The aim of this study was to determine a novel approach for predicting genomic instability via the combined assessment of adiposity, DNA damage, systemic inflammation, and vitamin D status. Subjects/methods We carried out a cross-sectional study with 132 participants, aged 10–18, recruited from schools and paediatric obesity clinics in London. Anthropometric assessments included BMI Z-score, waist and hip circumference, and body fat percentage via bioelectrical impedance. Inflammation and vitamin D levels in saliva were assessed by enzyme-linked immunosorbent assay. Oxidative DNA damage was determined via quantification of 8-hydroxy-2′-deoxyguanosine in urine. Exfoliated cells from the oral cavity were scored for genomic instability via the buccal cytome assay. Results As expected, comparisons between participants with obesity and normal range BMI showed significant differences in anthropometric measures (p < 0.001). Significant differences were also observed in some measures of genomic instability (p < 0.001). When examining relationships between variables for all participants, markers of adiposity positively correlated with acquired oxidative DNA damage (p < 0.01) and genomic instability (p < 0.001), and negatively correlated with vitamin D (p < 0.01). Multiple regression analyses identified obesity (p < 0.001), vitamin D (p < 0.001), and oxidative DNA damage (p < 0.05) as the three significant predictors of genomic instability. Conclusions Obesity, oxidative DNA damage, and vitamin D deficiency are significant predictors of genomic instability. Non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to the prioritisation and severity of clinical intervention measures.
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Lee, Kyoo-young, and Su Hyung Park. "Eukaryotic clamp loaders and unloaders in the maintenance of genome stability." Experimental & Molecular Medicine 52, no. 12 (December 2020): 1948–58. http://dx.doi.org/10.1038/s12276-020-00533-3.
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AbstractEukaryotic sliding clamp proliferating cell nuclear antigen (PCNA) plays a critical role as a processivity factor for DNA polymerases and as a binding and acting platform for many proteins. The ring-shaped PCNA homotrimer and the DNA damage checkpoint clamp 9-1-1 are loaded onto DNA by clamp loaders. PCNA can be loaded by the pentameric replication factor C (RFC) complex and the CTF18-RFC-like complex (RLC) in vitro. In cells, each complex loads PCNA for different purposes; RFC-loaded PCNA is essential for DNA replication, while CTF18-RLC-loaded PCNA participates in cohesion establishment and checkpoint activation. After completing its tasks, PCNA is unloaded by ATAD5 (Elg1 in yeast)-RLC. The 9-1-1 clamp is loaded at DNA damage sites by RAD17 (Rad24 in yeast)-RLC. All five RFC complex components, but none of the three large subunits of RLC, CTF18, ATAD5, or RAD17, are essential for cell survival; however, deficiency of the three RLC proteins leads to genomic instability. In this review, we describe recent findings that contribute to the understanding of the basic roles of the RFC complex and RLCs and how genomic instability due to deficiency of the three RLCs is linked to the molecular and cellular activity of RLC, particularly focusing on ATAD5 (Elg1).
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Morgan, Jonathan J., and Lisa J. Crawford. "The Ubiquitin Proteasome System in Genome Stability and Cancer." Cancers 13, no. 9 (May 6, 2021): 2235. http://dx.doi.org/10.3390/cancers13092235.
Full textAbstract:
Faithful DNA replication during cellular division is essential to maintain genome stability and cells have developed a sophisticated network of regulatory systems to ensure its integrity. Disruption of these control mechanisms can lead to loss of genomic stability, a key hallmark of cancer. Ubiquitination is one of the most abundant regulatory post-translational modifications and plays a pivotal role in controlling replication progression, repair of DNA and genome stability. Dysregulation of the ubiquitin proteasome system (UPS) can contribute to the initiation and progression of neoplastic transformation. In this review we provide an overview of the UPS and summarize its involvement in replication and replicative stress, along with DNA damage repair. Finally, we discuss how the UPS presents as an emerging source for novel therapeutic interventions aimed at targeting genomic instability, which could be utilized in the treatment and management of cancer.
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Zhao, Bo, Wei-dao Zhang, Ying-liang Duan, Yong-qing Lu, Yi-xian Cun, Chao-hui Li, Kun Guo, et al. "Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability." Cell Stem Cell 16, no. 6 (June 2015): 684–98. http://dx.doi.org/10.1016/j.stem.2015.03.017.
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Ting, Xia, Lu Xia, Jianguo Yang, Lin He, Wenzhe Si, Yongfeng Shang, and Luyang Sun. "USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair." Nucleic Acids Research 47, no. 18 (August 28, 2019): 9721–40. http://dx.doi.org/10.1093/nar/gkz726.
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Abstract How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.
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Marshall, Craig J., and Thomas J. Santangelo. "Archaeal DNA Repair Mechanisms." Biomolecules 10, no. 11 (October 23, 2020): 1472. http://dx.doi.org/10.3390/biom10111472.
Full textAbstract:
Archaea often thrive in environmental extremes, enduring levels of heat, pressure, salinity, pH, and radiation that prove intolerable to most life. Many environmental extremes raise the propensity for DNA damaging events and thus, impact DNA stability, placing greater reliance on molecular mechanisms that recognize DNA damage and initiate accurate repair. Archaea can presumably prosper in harsh and DNA-damaging environments in part due to robust DNA repair pathways but surprisingly, no DNA repair pathways unique to Archaea have been described. Here, we review the most recent advances in our understanding of archaeal DNA repair. We summarize DNA damage types and their consequences, their recognition by host enzymes, and how the collective activities of many DNA repair pathways maintain archaeal genomic integrity.