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      Rmi1 stimulates decatenation of double Holliday junctions during dissolution by Sgs1–Top3

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          Abstract

          A double Holliday junction (dHJ) is a central intermediate of homologous recombination which can be processed to yield crossover or non-crossover recombination products. To preserve genomic integrity, cells possess mechanisms to avoid crossing-over. Here we show that Saccharomyces cerevisiae Sgs1 and Top3 proteins are sufficient to migrate and disentangle a dHJ to produce exclusively non-crossover recombination products, in a reaction termed “dissolution”. Furthermore, we show that Rmi1 stimulates dHJ dissolution at low Sgs1–Top3 protein concentrations, although it has no effect on the initial rate of Holliday junction (HJ) migration. Rmi1 serves to stimulate DNA decatenation, thereby removing the last linkages between the repaired and template DNA molecules. Dissolution of a dHJ is a highly efficient and concerted alternative to nucleolytic resolution that prevents crossing over of chromosomes during recombinational DNA repair in mitotic cells, and thereby contributes to genomic integrity.

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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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            Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast.

            Grzegorz Ira, Anna Malkova, Giordano Liberi … (2003)
            Very few gene conversions in mitotic cells are associated with crossovers, suggesting that these events are regulated. This may be important for the maintenance of genetic stability. We have analyzed the relationship between homologous recombination and crossing-over in haploid budding yeast and identified factors involved in the regulation of crossover outcomes. Gene conversions unaccompanied by a crossover appear 30 min before conversions accompanied by exchange, indicating that there are two different repair mechanisms in mitotic cells. Crossovers are rare (5%), but deleting the BLM/WRN homolog, SGS1, or the SRS2 helicase increases crossovers 2- to 3-fold. Overexpressing SRS2 nearly eliminates crossovers, whereas overexpression of RAD51 in srs2Delta cells almost completely eliminates the noncrossover recombination pathway. We suggest Sgs1 and its associated topoisomerase Top3 remove double Holliday junction intermediates from a crossover-producing repair pathway, thereby reducing crossovers. Srs2 promotes the noncrossover synthesis-dependent strand-annealing (SDSA) pathway, apparently by regulating Rad51 binding during strand exchange.
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              A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes.

              R Krishna Chaganti, J German, S Schønberg (1974)
              Dividing cells from persons with Bloom's syndrome, an autosomal recessive disorder of growth, exhibit increased numbers of chromatid breaks and rearrangements. A highly characteristic feature of the chromosome instability in this syndrome is the tendency for exchanges to occur between chromatids of homologous chromosomes at homologous sites. In the present experiments, a cytogenetic technique by which the sister chromatids of a metaphase chromosome are stained differentially has been used to demonstrate a striking and possibly specific, but hitherto unrecognized, increase in the frequency with which sister chromatids also exchange segments. The cells were grown in bromodeoxyuridine and stained with 33258 Hoechst and Giemsa. Whereas phytohemagglutinin-stimulated lymphocytes from normal controls had a mean of 6.9 sister chromatid exchanges per metaphase (range 1-14), those from persons with Bloom's syndrome had a mean of 89.0 (range 45-162). Normal frequencies of sister chromatid exchanges were found in cells heterozygous for the Bloom's syndrome gene, and also in cells either homozygous or heterozygous for the genes of the Louis-Bar (ataxia telangiectasia) syndrome and Fanconi's anemia, two other rare disorders characterized by chromosome instability. In a differentially stained chromatid interchange configuration discovered during the study, it was possible to determine the new distribution of both sister and non-sister-but-homologous chromatids that had resulted from numerous exchanges. By following shifts in the pattern of staining from chromatid to chromatid, visual evidence was obtained that the quadriradial configurations long recognized as characteristic of Bloom's syndrome represent exchanges between homologous chromosomes, apparently at homologous points. We postulate that the increase in the frequency of exchanges between nonsister-but-homologous chromatids and those between sister chromatids in Bloom's syndrome represents aspects of one and the same disturbance. A study of this phenomenon in relation to the clinical features of Bloom's syndrome may be helpful eventually in understanding the biological significance of chromatid exchange in somatic cells.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 16 September 2010
                Publication date (Electronic): 10 October 2010
                Publication date (Print): November 2010
                Publication date PMC-release: 1 May 2011
                Volume: 17
                Issue: 11
                Pages: 1377-1382
                Affiliations
                [1 ]Departments of Microbiology and of Molecular and Cellular Biology, University of California, Davis, Davis, USA.
                [2 ]Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
                Author notes
                Address correspondence to: Stephen C. Kowalczykowski, Department of Microbiology, University of California, Davis, One Shields Ave, Davis, CA 95616-8665. Phone: 530-752-5938; Fax: 530-752-5939; sckowalczykowski@ 123456ucdavis.edu
                [3]

                Both authors contributed equally to this study.

                Article
                Manuscript ID: nihpa232799
                DOI: 10.1038/nsmb.1919
                PMC ID: 2988882
                PubMed ID: 20935631
                SO-VID: 43d88f8f-8675-40e6-a77c-17dfb32de837
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM062653-31 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM062653-30 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM041347-14 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM041347-13 ||GM
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
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                ScienceOpen disciplines: Molecular biology

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