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Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1
Tracy L Callender1, Raphaelle Laureau2,3, Lihong Wan1
1Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, United States of America.
Abstract:
During meiosis, programmed double strand breaks (DSBs) are repaired preferentially between homologs to generate crossovers that promote proper chromosome segregation at Meiosis I. In many organisms, there are two strand exchange proteins, Rad51 and the meiosis-specific Dmc1, required for interhomolog (IH) bias. This bias requires the presence, but not the strand exchange activity of Rad51, while Dmc1 is responsible for the bulk of meiotic recombination. How these activities are regulated is less well established. In dmc1Δ mutants, Rad51 is actively inhibited, thereby resulting in prophase arrest due to unrepaired DSBs triggering the meiotic recombination checkpoint. This inhibition is dependent upon the meiosis-specific kinase Mek1 and occurs through two different mechanisms that prevent complex formation with the Rad51 accessory factor Rad54: (i) phosphorylation of Rad54 by Mek1 and (ii) binding of Rad51 by the meiosis-specific protein Hed1. An open question has been why inhibition of Mek1 affects Hed1 repression of Rad51. This work shows that Hed1 is a direct substrate of Mek1. Phosphorylation of Hed1 at threonine 40 helps suppress Rad51 activity in dmc1Δ mutants by promoting Hed1 protein stability. Rad51-mediated recombination occurring in the absence of Hed1 phosphorylation results in a significant increase in non-exchange chromosomes despite wild-type levels of crossovers, confirming previous results indicating a defect in crossover assurance. We propose that Rad51 function in meiosis is regulated in part by the coordinated phosphorylation of Rad54 and Hed1 by Mek1.
Insights
Meiosis relies on programmed DNA breaks for chromosome repair. This study reveals Mek1 kinase regulates Rad51 activity via Hed1 phosphorylation, ensuring proper crossover formation and chromosome segregation.
Area of Science:
- Genetics
- Molecular Biology
- Cell Biology
Background:
- Meiosis requires programmed double-strand breaks (DSBs) repaired preferentially between homologs to ensure proper chromosome segregation.
- Rad51 and Dmc1 are key proteins for interhomolog bias during meiotic recombination.
- In dmc1 mutants, Rad51 is inhibited by the kinase Mek1 through Rad54 phosphorylation and Hed1 binding, preventing recombination and causing prophase arrest.
Purpose of the Study:
- To investigate the mechanism by which Mek1 regulates Rad51 activity, specifically its interaction with Hed1.
- To elucidate the role of Hed1 phosphorylation by Mek1 in controlling Rad51 function during meiosis.
Main Methods:
- Investigated the interaction between Mek1, Hed1, and Rad51 in yeast mutants.
- Utilized biochemical assays to determine if Hed1 is a direct substrate of Mek1.
- Analyzed the effect of Hed1 phosphorylation status on Rad51 activity and meiotic recombination outcomes.
Main Results:
- Demonstrated that Hed1 is a direct substrate of Mek1, with phosphorylation occurring at threonine 40.
- Showed that Mek1-mediated phosphorylation of Hed1 enhances its stability and suppresses Rad51 activity in dmc1Δ mutants.
- Found that unrepaired Hed1 leads to increased non-exchange chromosomes, indicating a defect in crossover assurance.
Conclusions:
- Mek1 kinase plays a crucial role in regulating meiotic recombination by phosphorylating both Rad54 and Hed1.
- Coordinated phosphorylation of Rad54 and Hed1 by Mek1 is essential for suppressing Rad51 activity and ensuring proper crossover formation.
- This regulatory mechanism is vital for accurate chromosome segregation during meiosis.
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