Regulation of the MLH1-MLH3 endonuclease in meiosis.

Autor: Cannavo E; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland., Sanchez A; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland., Anand R; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland., Ranjha L; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland., Hugener J; Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland., Adam C; Institut Curie, PSL Research University, CNRS UMR3244, Paris, France.; Paris Sorbonne Université, Paris, France., Acharya A; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland.; Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland., Weyland N; Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland., Aran-Guiu X; Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK., Charbonnier JB; I2BC, iBiTec-S, CEA, CNRS UMR 9198, Université Paris-Sud, Gif-sur-Yvette, France.; Université Paris Sud, Orsay, France., Hoffmann ER; Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.; DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Borde V; Institut Curie, PSL Research University, CNRS UMR3244, Paris, France.; Paris Sorbonne Université, Paris, France., Matos J; Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland., Cejka P; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland. petr.cejka@irb.usi.ch.; Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland. petr.cejka@irb.usi.ch.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Oct; Vol. 586 (7830), pp. 618-622. Date of Electronic Publication: 2020 Aug 19.
DOI: 10.1038/s41586-020-2592-2
Abstrakt: During prophase of the first meiotic division, cells deliberately break their DNA 1 . These DNA breaks are repaired by homologous recombination, which facilitates proper chromosome segregation and enables the reciprocal exchange of DNA segments between homologous chromosomes 2 . A pathway that depends on the MLH1-MLH3 (MutLγ) nuclease has been implicated in the biased processing of meiotic recombination intermediates into crossovers by an unknown mechanism 3-7 . Here we have biochemically reconstituted key elements of this pro-crossover pathway. We show that human MSH4-MSH5 (MutSγ), which supports crossing over 8 , binds branched recombination intermediates and associates with MutLγ, stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutSγ directly stimulates DNA cleavage by the MutLγ endonuclease. MutLγ activity is further stimulated by EXO1, but only when MutSγ is present. Replication factor C (RFC) and the proliferating cell nuclear antigen (PCNA) are additional components of the nuclease ensemble, thereby triggering crossing-over. Saccharomyces cerevisiae strains in which MutLγ cannot interact with PCNA present defects in forming crossovers. Finally, the MutLγ-MutSγ-EXO1-RFC-PCNA nuclease ensemble preferentially cleaves DNA with Holliday junctions, but shows no canonical resolvase activity. Instead, it probably processes meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points 9 . As DNA nicking by MutLγ depends on its co-factors, the asymmetric distribution of MutSγ and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. This mode of MutLγ nuclease activation might explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes 4 .
Databáze: MEDLINE
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