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      Noncanonical views of homology-directed DNA repair

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          Abstract

          While gene conversion and classical nonhomologous end-joining are the most physiologically predominant forms of DNA repair mechanisms, emerging lines of evidence suggest the usage of several noncanonical homology-directed repair (HDR) pathways in both prokaryotes and eukaryotes in different contexts. Here, Verma and Greenberg review how these alternative HDR pathways are executed.

          Abstract

          DNA repair is essential to maintain genomic integrity and initiate genetic diversity. While gene conversion and classical nonhomologous end-joining are the most physiologically predominant forms of DNA repair mechanisms, emerging lines of evidence suggest the usage of several noncanonical homology-directed repair (HDR) pathways in both prokaryotes and eukaryotes in different contexts. Here we review how these alternative HDR pathways are executed, specifically focusing on the determinants that dictate competition between them and their relevance to cancers that display complex genomic rearrangements or maintain their telomeres by homology-directed DNA synthesis.

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          Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

          Hannah L. Farmer, Nuala McCabe, Christopher J. Lord … (2005)
          BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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            Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.

            Helen E. Bryant, Niklas Schultz, Huw Thomas … (2005)
            Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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              Mechanisms of change in gene copy number.

              P Hastings, James R. Lupski, Susan M. Rosenberg … (2009)
              Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
              Article 0 comments Cited 439 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 15 May 2016
                Volume: 30
                Issue: 10
                Pages: 1138-1154
                Affiliations
                Department of Cancer Biology, Department Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                Author notes
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.280545.116
                PMC ID: 4888836
                PubMed ID: 27222516
                SO-VID: b7c085b6-c9b9-4140-877e-9ed13849670c
                Copyright © © 2016 Verma and Greenberg; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 17
                Funding
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: GM101149
                Award ID: CA17494
                Funded by: Abramson Family Cancer Research Institute http://dx.doi.org/10.13039/100008435
                Categories
                Subject: 1
                Subject: Review

                Keywords: alt,dna repair,homologous recombination,telomere,break-induced replication
                Data availability:
                Keywords: alt, dna repair, homologous recombination, telomere, break-induced replication

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