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Updated: Dec 27, 2025
Frequency and Distribution of Crossovers in Caenorhabditis elegans Meiosis by SNP Genotyping using Real-time PCR
Published on: July 11, 2025
Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over
Wei He1, H B D Prasada Rao1, Shangming Tang1
1Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA; Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA.
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.
Insights
Meiotic crossing over relies on the MutSγ complex. Its activation involves neutralizing a degradation tag on Msh4 via phosphorylation, controlled by the Cdc7 kinase, ensuring accurate chromosome segregation.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Crossover recombination is crucial for accurate chromosome segregation during meiosis.
- The MutSγ complex (Msh4-Msh5) stabilizes recombination intermediates to promote crossing over.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing MutSγ activity and meiotic crossing over.
- To investigate the role of protein degradation and phosphorylation in MutSγ function.
Main Methods:
- Proteolysis assays
- Kinase assays using Dbf4-dependent kinase Cdc7 (DDK)
- Genetic analysis of Msh4 phosphorylation mutants
- Overexpression studies
- Analysis of double-Holliday Junction intermediates
Main Results:
- MutSγ is initially inactivated by an N-terminal degron on Msh4, targeting it for proteasomal degradation.
- Activation requires DDK-mediated phosphorylation of Msh4, neutralizing the degron.
- DDK targets MutSγ only after binding to nascent joint molecules on synapsing chromosomes.
- Msh4 phosphorylation facilitates crossover-biased resolution of double-Holliday Junctions.
Conclusions:
- Regulated proteolysis of Msh4 is a key mechanism controlling MutSγ activity.
- Msh4 phosphorylation by DDK is essential for enabling crossover formation and proper chromosome segregation.
- Steady-state levels of Msh4, influenced by degradation, are critical for meiotic crossing over.
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