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      Mechanisms of damage tolerance and repair during DNA replication

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      Author(s): ,
      Publication date (Electronic):
      Journal: Nucleic Acids Research
      Publisher: Oxford University Press

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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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          cGAS surveillance of micronuclei links genome instability to innate immunity

          Karen J. Mackenzie, Paula Carroll, Carol-Anne Martin … (2017)
          Summary DNA is strictly compartmentalised within the nucleus to prevent autoimmunity1; despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage2–6. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localises to micronuclei arising from genome instability in a model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. These micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by their own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis7, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS binds to and is activated by chromatin and, consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA-damage are cell-cycle dependent. Furthermore, by combining live-cell laser microdissection with single cell transcriptomics, we establish that induction of interferon stimulated gene expression occurs in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, cGAS recognition of micronuclei may act as a cell-intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes.
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            RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.

            Carsten Hoege, Boris Pfander, George-Lucian Moldovan … (2002)
            The RAD6 pathway is central to post-replicative DNA repair in eukaryotic cells; however, the machinery and its regulation remain poorly understood. Two principal elements of this pathway are the ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which are recruited to chromatin by the RING-finger proteins RAD18 and RAD5, respectively. Here we show that UBC9, a small ubiquitin-related modifier (SUMO)-conjugating enzyme, is also affiliated with this pathway and that proliferating cell nuclear antigen (PCNA) -- a DNA-polymerase sliding clamp involved in DNA synthesis and repair -- is a substrate. PCNA is mono-ubiquitinated through RAD6 and RAD18, modified by lysine-63-linked multi-ubiquitination--which additionally requires MMS2, UBC13 and RAD5--and is conjugated to SUMO by UBC9. All three modifications affect the same lysine residue of PCNA, suggesting that they label PCNA for alternative functions. We demonstrate that these modifications differentially affect resistance to DNA damage, and that damage-induced PCNA ubiquitination is elementary for DNA repair and occurs at the same conserved residue in yeast and humans.
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              Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.

              J. Murai, S.-y. N. Huang, B Das … (2012)
              Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However, the mechanism of action of PARP inhibitors with regard to their effects in cancer cells is not fully understood. In this study, we show that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP-DNA complexes were more cytotoxic than unrepaired SSBs caused by PARP inactivation, arguing that PARP inhibitors act in part as poisons that trap PARP enzyme on DNA. Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) > olaparib (AZD-2281) > veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. We also analyzed repair pathways for PARP-DNA complexes using 30 genetically altered avian DT40 cell lines with preestablished deletions in specific DNA repair genes. This analysis revealed that, in addition to homologous recombination, postreplication repair, the Fanconi anemia pathway, polymerase β, and FEN1 are critical for repairing trapped PARP-DNA complexes. In summary, our study provides a new mechanistic foundation for the rational application of PARP inhibitors in cancer therapy. ©2012 AACR.
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                Author and article information

                Contributors
                Mohamed Elsaid Ashour
                Nima Mosammaparast:
                ORCID: https://orcid.org/0000-0001-5453-5914
                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date Collection: 06 April 2021
                Publication date (Electronic): 08 March 2021
                Publication date PMC-release: 08 March 2021
                Volume: 49
                Issue: 6
                Pages: 3033-3047
                Affiliations
                Department of Pathology & Immunology, Washington University in St. Louis School of Medicine , St. Louis, MO 63110, USA
                Department of Pathology & Immunology, Washington University in St. Louis School of Medicine , St. Louis, MO 63110, USA
                Author notes
                To whom correspondence should be addressed. Tel: +1 314 747 5472; Email: nima@ 123456wustl.edu
                Author information
                https://orcid.org/0000-0001-5453-5914
                Article
                Publisher ID: gkab101
                DOI: 10.1093/nar/gkab101
                PMC ID: 8034635
                PubMed ID: 33693881
                SO-VID: 341acb7d-5b12-4957-b389-a38d92d61c90
                Copyright © © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                Date accepted : 02 March 2021
                Date revision received : 28 January 2021
                Date received : 16 November 2020
                Page count
                Pages: 15
                Funding
                Funded by: NIH, DOI 10.13039/100000002;
                Award ID: R01 CA193318
                Award ID: R01 CA227001
                Funded by: Structural Cell Biology of DNA Repair Machines Program;
                Award ID: P01 CA092584
                Funded by: American Cancer Society, DOI 10.13039/100000048;
                Award ID: RSG-18-156-01-DMC
                Funded by: Siteman Investment Program;
                Categories
                Subject: AcademicSubjects/SCI00010
                Subject: Survey and Summary

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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