PMID- 32130890 OWN - NLM STAT- MEDLINE DCOM- 20200722 LR - 20211204 IS - 1097-4164 (Electronic) IS - 1097-2765 (Print) IS - 1097-2765 (Linking) VI - 78 IP - 1 DP - 2020 Apr 2 TI - Regulated Proteolysis of MutSgamma Controls Meiotic Crossing Over. PG - 168-183.e5 LID - S1097-2765(20)30071-X [pii] LID - 10.1016/j.molcel.2020.02.001 [doi] AB - Crossover recombination is essential for accurate chromosome segregation during meiosis. The MutSgamma complex, Msh4-Msh5, facilitates crossing over by binding and stabilizing nascent recombination intermediates. We show that these activities are governed by regulated proteolysis. MutSgamma is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable by directly targeting proteasomal degradation. Activation of MutSgamma requires the Dbf4-dependent kinase Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Genetic requirements for Msh4 phosphorylation indicate that DDK targets MutSgamma only after it has bound to nascent joint molecules (JMs) in the context of synapsing chromosomes. Overexpression studies confirm that the steady-state level of Msh4, not phosphorylation per se, is the critical determinant for crossing over. At the DNA level, Msh4 phosphorylation enables the formation and crossover-biased resolution of double-Holliday Junction intermediates. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossing over. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - He, Wei AU - He W AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Rao, H B D Prasada AU - Rao HBDP AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Tang, Shangming AU - Tang S AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Bhagwat, Nikhil AU - Bhagwat N AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Kulkarni, Dhananjaya S AU - Kulkarni DS AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Ma, Yunmei AU - Ma Y AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Chang, Maria A W AU - Chang MAW AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Hall, Christie AU - Hall C AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Bragg, Junxi Wang AU - Bragg JW AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Manasca, Harrison S AU - Manasca HS AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Baker, Christa AU - Baker C AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Verhees, Gerrik F AU - Verhees GF AD - Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA. FAU - Ranjha, Lepakshi AU - Ranjha L AD - Institute for Research in Biomedicine, Universita della Svizzera italiana, Bellinzona, Switzerland. FAU - Chen, Xiangyu AU - Chen X AD - Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA. FAU - Hollingsworth, Nancy M AU - Hollingsworth NM AD - Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA. FAU - Cejka, Petr AU - Cejka P AD - Institute for Research in Biomedicine, Universita della Svizzera italiana, Bellinzona, Switzerland. FAU - Hunter, Neil AU - Hunter N AD - Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA; Department of Molecular & Cellular Biology, University of California, Davis, Davis, California, USA; Department of Cell Biology & Human Anatomy, University of California, Davis, Davis, California, USA. Electronic address: nhunter@ucdavis.edu. LA - eng GR - R01 GM050717/GM/NIGMS NIH HHS/United States GR - R01 GM074223/GM/NIGMS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200303 PL - United States TA - Mol Cell JT - Molecular cell JID - 9802571 RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (MSH4 protein, S cerevisiae) RN - 0 (Saccharomyces cerevisiae Proteins) RN - EC 2.7.1.- (CDC7 protein, S cerevisiae) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Cell Cycle Proteins/metabolism MH - Chromosome Pairing MH - *Crossing Over, Genetic MH - DNA-Binding Proteins/chemistry/*metabolism MH - Meiosis/*genetics MH - Phosphorylation MH - Proteasome Endopeptidase Complex/*metabolism MH - Protein Serine-Threonine Kinases/metabolism MH - Proteolysis MH - Saccharomyces cerevisiae Proteins/chemistry/*metabolism PMC - PMC7289160 MID - NIHMS1596028 OTO - NOTNLM OT - Cdc7 OT - Holliday Junction OT - MutS OT - aneuploidy OT - chromosome OT - crossing over OT - degron OT - homologous recombination OT - meiosis OT - proteasome COIS- Declaration of Interests The authors declare no competing interests. EDAT- 2020/03/05 06:00 MHDA- 2020/07/23 06:00 PMCR- 2020/06/11 CRDT- 2020/03/05 06:00 PHST- 2019/10/21 00:00 [received] PHST- 2020/01/03 00:00 [revised] PHST- 2020/01/31 00:00 [accepted] PHST- 2020/03/05 06:00 [pubmed] PHST- 2020/07/23 06:00 [medline] PHST- 2020/03/05 06:00 [entrez] PHST- 2020/06/11 00:00 [pmc-release] AID - S1097-2765(20)30071-X [pii] AID - 10.1016/j.molcel.2020.02.001 [doi] PST - ppublish SO - Mol Cell. 2020 Apr 2;78(1):168-183.e5. doi: 10.1016/j.molcel.2020.02.001. Epub 2020 Mar 3.