65
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Processing of joint molecule intermediates by structure-selective endonucleases during homologous recombination in eukaryotes

      1 , , 1 , 2

      Chromosoma

      Springer-Verlag

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Homologous recombination is required for maintaining genomic integrity by functioning in high-fidelity repair of DNA double-strand breaks and other complex lesions, replication fork support, and meiotic chromosome segregation. Joint DNA molecules are key intermediates in recombination and their differential processing determines whether the genetic outcome is a crossover or non-crossover event. The Holliday model of recombination highlights the resolution of four-way DNA joint molecules, termed Holliday junctions, and the bacterial Holliday junction resolvase RuvC set the paradigm for the mechanism of crossover formation. In eukaryotes, much effort has been invested in identifying the eukaryotic equivalent of bacterial RuvC, leading to the discovery of a number of DNA endonucleases, including Mus81–Mms4/EME1, Slx1–Slx4/BTBD12/MUS312, XPF–ERCC1, and Yen1/GEN1. These nucleases exert different selectivity for various DNA joint molecules, including Holliday junctions. Their mutant phenotypes and distinct species-specific characteristics expose a surprisingly complex system of joint molecule processing. In an attempt to reconcile the biochemical and genetic data, we propose that nicked junctions constitute important in vivo recombination intermediates whose processing determines the efficiency and outcome (crossover/non-crossover) of homologous recombination.

          Related collections

          Most cited references 130

          • Record: found
          • Abstract: found
          • Article: not found

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

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The single-end invasion: an asymmetric intermediate at the double-strand break to double-holliday junction transition of meiotic recombination.

            We identify a novel meiotic recombination intermediate, the single-end invasion (SEI), which occurs during the transition from double-strand breaks (DSBs) to double-Holliday junction (dHJs). SEIs are products of strand exchange between one DSB end and its homolog. The structural asymmetry of SEIs indicates that the two ends of a DSB interact with the homolog in temporal succession, via structurally (and thus biochemically) distinct processes. SEIs arise surprisingly late in prophase, concomitant with synaptonemal complex (SC) formation. These and other data imply that SEIs are preceded by nascent DSB-partner intermediates, which then undergo selective differentiation into crossover and noncrossover types, with SC formation and strand exchange as downstream consequences. Late occurrence of strand exchange provides opportunity to reverse recombinational fate even after homologs are coaligned and/or synapsed. This feature can explain crossover suppression between homeologous and structurally heterozygous chromosomes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.

              Structure-specific endonucleases resolve DNA secondary structures generated during DNA repair and recombination. The yeast 5' flap endonuclease Slx1-Slx4 has received particular attention with the finding that Slx4 has Slx1-independent key functions in genome maintenance. Although Slx1 is a highly conserved protein in eukaryotes, no orthologs of Slx4 were reported other than in fungi. Here we report the identification of Slx4 orthologs in metazoa, including fly MUS312, essential for meiotic recombination, and human BTBD12, an ATM/ATR checkpoint kinase substrate. Human SLX1-SLX4 displays robust Holliday junction resolvase activity in addition to 5' flap endonuclease activity. Depletion of SLX1 and SLX4 results in 53BP1 foci accumulation and H2AX phosphorylation as well as cellular hypersensitivity to MMS. Furthermore, we show that SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair. We propose that SLX4 acts as a docking platform for multiple structure-specific endonucleases.
                Bookmark

                Author and article information

                Contributors
                +1-530-7523001 , +1-530-7523011 , wdheyer@ucdavis.edu
                Journal
                Chromosoma
                Chromosoma
                Springer-Verlag (Berlin/Heidelberg )
                0009-5915
                1432-0886
                11 January 2011
                11 January 2011
                April 2011
                : 120
                : 2
                : 109-127
                Affiliations
                [1 ]Department of Microbiology, University of California—Davis, Davis, CA 95616 USA
                [2 ]Department of Molecular and Cellular Biology, University of California—Davis, Davis, CA 95616 USA
                Author notes

                Communicated by E. Nigg

                Article
                304
                10.1007/s00412-010-0304-7
                3057012
                21369956
                © The Author(s) 2011
                Categories
                Review
                Custom metadata
                © Springer-Verlag 2011

                Genetics

                Comments

                Comment on this article