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      Mechanism of homologous recombination: mediators and helicases take on regulatory functions

      Author(s): ,
      Publication date (Electronic):
      Journal: Nature Reviews Molecular Cell Biology
      Publisher: Springer Science and Business Media LLC

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          Abstract

          Homologous recombination (HR) is an important mechanism for the repair of damaged chromosomes, for preventing the demise of damaged replication forks, and for several other aspects of chromosome maintenance. As such, HR is indispensable for genome integrity, but it must be regulated to avoid deleterious events. Mutations in the tumour-suppressor protein BRCA2, which has a mediator function in HR, lead to cancer formation. DNA helicases, such as Bloom's syndrome protein (BLM), regulate HR at several levels, in attenuating unwanted HR events and in determining the outcome of HR. Defects in BLM are also associated with the cancer phenotype. The past several years have witnessed dramatic advances in our understanding of the mechanism and regulation of HR.

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          The Bloom's syndrome helicase suppresses crossing over during homologous recombination.

          Leonard Wu, Ian D. Hickson (2003)
          Mutations in BLM, which encodes a RecQ helicase, give rise to Bloom's syndrome, a disorder associated with cancer predisposition and genomic instability. A defining feature of Bloom's syndrome is an elevated frequency of sister chromatid exchanges. These arise from crossing over of chromatid arms during homologous recombination, a ubiquitous process that exists to repair DNA double-stranded breaks and damaged replication forks. Whereas crossing over is required in meiosis, in mitotic cells it can be associated with detrimental loss of heterozygosity. BLM forms an evolutionarily conserved complex with human topoisomerase IIIalpha (hTOPO IIIalpha), which can break and rejoin DNA to alter its topology. Inactivation of homologues of either protein leads to hyper-recombination in unicellular organisms. Here, we show that BLM and hTOPO IIIalpha together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which we term double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom's syndrome. These results have wider implications for our understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.
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            The Bloom's syndrome gene product is homologous to RecQ helicases.

            N A Ellis, J Groden, T Ye … (1995)
            The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.
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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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                Author and article information

                Journal
                Title: Nature Reviews Molecular Cell Biology
                Abbreviated Title: Nat Rev Mol Cell Biol
                Publisher: Springer Science and Business Media LLC
                ISSN (Print): 1471-0072
                ISSN (Electronic): 1471-0080
                Publication date Created: October 2006
                Publication date (Electronic): August 23 2006
                Publication date (Print): October 2006
                Volume: 7
                Issue: 10
                Pages: 739-750
                Article
                DOI: 10.1038/nrm2008
                PubMed ID: 16926856
                SO-VID: 2bcdb40c-182f-4dba-9512-1d7d9afc857c
                Copyright © © 2006
                License:

                http://www.springer.com/tdm

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