Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over

Wei He, H. B.D.Prasada Rao, Shangming Tang, Nikhil Bhagwat, Dhananjaya S. Kulkarni, Yunmei Ma, Maria A.W. Chang, Christie Hall, Junxi Wang Bragg, Harrison S. Manasca, Christa Baker, Gerrik F. Verhees, Lepakshi Ranjha, Xiangyu Chen, Nancy M. Hollingsworth, Petr Cejka, Neil Hunter

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Crossover recombination is essential for accurate chromosome segregation during meiosis. The MutSγ complex, Msh4-Msh5, facilitates crossing over by binding and stabilizing nascent recombination intermediates. We show that these activities are governed by regulated proteolysis. MutSγ 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 MutSγ 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 MutSγ 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.

Original languageEnglish (US)
Pages (from-to)168-183.e5
JournalMolecular Cell
Volume78
Issue number1
DOIs
StatePublished - Apr 2 2020

Keywords

  • aneuploidy
  • Cdc7
  • chromosome
  • crossing over
  • degron
  • Holliday Junction
  • homologous recombination
  • meiosis
  • MutS
  • proteasome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    He, W., Rao, H. B. D. P., Tang, S., Bhagwat, N., Kulkarni, D. S., Ma, Y., Chang, M. A. W., Hall, C., Bragg, J. W., Manasca, H. S., Baker, C., Verhees, G. F., Ranjha, L., Chen, X., Hollingsworth, N. M., Cejka, P., & Hunter, N. (2020). Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over. Molecular Cell, 78(1), 168-183.e5. https://doi.org/10.1016/j.molcel.2020.02.001