Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over

• DOI: 10.1016/j.molcel.2020.02.001
• Publication Date: 2020-03-03T16:49:12Z
• Authors: Wei He; H.B.D. Prasada Rao; Shangming Tang; Nikhil Bhagwat; Dhananjaya S. Kul...; 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. Hollings...; Petr Cejka; Neil Hunter
• Keywords: 570; Proteasome Endopeptidase Complex; Biomedical and clinical sciences; Saccharomyces cerevisiae Proteins; 1.1 Normal biological development and functioning; MutS; crossing over; homologous recombination; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Medical and Health Sciences; Cdc7; 03 medical and health sciences; Genetic; Genetics; Crossing Over; meiosis; aneuploidy; chromosome; Crossing Over, Genetic; Phosphorylation; 0303 health sciences; Holliday Junction; Health sciences; Biological Sciences; degron; DNA-Binding Proteins; Biological sciences; Chromosome Pairing; Meiosis; proteasome; Proteolysis; Biochemistry and Cell Biology; Generic health relevance; Developmental Biology

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.