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      Homologous recombination and the repair of DNA double-strand breaks

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      Journal: Journal of Biological Chemistry
      Publisher: American Society for Biochemistry & Molecular Biology (ASBMB)

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          Abstract

          <p class="first" id="d8820712e159">Homologous recombination enables the cell to access and copy intact DNA sequence information in <i>trans</i>, particularly to repair DNA damage affecting both strands of the double helix. Here, we discuss the DNA transactions and enzymatic activities required for this elegantly orchestrated process in the context of the repair of DNA double-strand breaks in somatic cells. This includes homology search, DNA strand invasion, repair DNA synthesis, and restoration of intact chromosomes. Aspects of DNA topology affecting individual steps are highlighted. Overall, recombination is a dynamic pathway with multiple metastable and reversible intermediates designed to achieve DNA repair with high fidelity. </p>

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          BRCA2 is required for homology-directed repair of chromosomal breaks.

          M Moynahan, A. Pierce, M Jasin (2001)
          The BRCA2 tumor suppressor has been implicated in the maintenance of chromosomal stability through a function in DNA repair. In this report, we examine human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, we find that BRCA2 mutant cell lines are recombination deficient, such that homology-directed repair is reduced 6- to >100-fold, depending on the cell line. Thus, BRCA2 is essential for efficient homology-directed repair, presumably in conjunction with the Rad51 recombinase. We propose that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage.
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            DNA helicase Srs2 disrupts the Rad51 presynaptic filament.

            Lumir Krejci, Stephen Van Komen, Ying Li … (2003)
            Mutations in the Saccharomyces cerevisiae gene SRS2 result in the yeast's sensitivity to genotoxic agents, failure to recover or adapt from DNA damage checkpoint-mediated cell cycle arrest, slow growth, chromosome loss, and hyper-recombination. Furthermore, double mutant strains, with mutations in DNA helicase genes SRS2 and SGS1, show low viability that can be overcome by inactivating recombination, implying that untimely recombination is the cause of growth impairment. Here we clarify the role of SRS2 in recombination modulation by purifying its encoded product and examining its interactions with the Rad51 recombinase. Srs2 has a robust ATPase activity that is dependent on single-stranded DNA (ssDNA) and binds Rad51, but the addition of a catalytic quantity of Srs2 to Rad51-mediated recombination reactions causes severe inhibition of these reactions. We show that Srs2 acts by dislodging Rad51 from ssDNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the Rad51 presynaptic filament efficiently. Our findings have implications for the basis of Bloom's and Werner's syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated ageing.
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              The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments.

              Xavier Veaute, Josette Jeusset, Christine Soustelle … (2003)
              Homologous recombination is a ubiquitous process with key functions in meiotic and vegetative cells for the repair of DNA breaks. It is initiated by the formation of single-stranded DNA on which recombination proteins bind to form a nucleoprotein filament that is active in searching for homology, in the formation of joint molecules and in the exchange of DNA strands. This process contributes to genome stability but it is also potentially dangerous to cells if intermediates are formed that cannot be processed normally and thus are toxic or generate genomic rearrangements. Cells must therefore have developed strategies to survey recombination and to prevent the occurrence of such deleterious events. In Saccharomyces cerevisiae, genetic data have shown that the Srs2 helicase negatively modulates recombination, and later experiments suggested that it reverses intermediate recombination structures. Here we show that DNA strand exchange mediated in vitro by Rad51 is inhibited by Srs2, and that Srs2 disrupts Rad51 filaments formed on single-stranded DNA. These data provide an explanation for the anti-recombinogenic role of Srs2 in vivo and highlight a previously unknown mechanism for recombination control.
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                Author and article information

                Journal
                Title: Journal of Biological Chemistry
                Abbreviated Title: J. Biol. Chem.
                Publisher: American Society for Biochemistry & Molecular Biology (ASBMB)
                ISSN (Print): 0021-9258
                ISSN (Electronic): 1083-351X
                Publication date Created: July 06 2018
                Publication date Created: July 06 2018
                Publication date (Print): July 06 2018
                Publication date (Electronic): March 29 2018
                Volume: 293
                Issue: 27
                Pages: 10524-10535
                Article
                DOI: 10.1074/jbc.TM118.000372
                PMC ID: 6036207
                PubMed ID: 29599286
                SO-VID: 16265ccf-12ed-484e-8a41-ebfafc85c0ff
                Copyright © © 2018
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