A Meiotic Checkpoint Alters Repair Partner Bias to Permit Inter-sister Repair of Persistent DSBs

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• Accurate meiotic chromosome segregation is crucial for preventing aneuploidy and developmental defects.
• Meiotic crossovers, initiated by double-strand breaks (DSBs), are essential for homologous chromosome pairing and segregation.
• The mechanisms protecting meiotic cells from unscheduled DNA breaks are not well understood.

Purpose of the Study:

• To investigate the checkpoint response to persistent meiotic double-strand breaks (DSBs) in *C. elegans*.
• To elucidate the role of synaptonemal complex (SC) phosphorylation in DNA repair partner choice during meiosis.
• To identify key proteins involved in safeguarding the germline against meiotic DSBs.

Main Methods:

• Utilized *C. elegans* as a model organism.
• Investigated checkpoint response to ionizing radiation (IR) and unrepaired meiotic DSBs.
• Analyzed the phosphorylation status and function of the core SC component SYP-1.
• Studied the genetic interactions between SYP-1 phosphorylation mutants and *brc-1* (BRCA1) mutants.

Main Results:

• Identified a checkpoint response that phosphorylates the SC to switch repair from homolog to sister chromatid.
• Demonstrated that SYP-1 phosphorylation is a key event in this checkpoint response.
• Showed that failure to phosphorylate or dephosphorylate SYP-1 leads to chromosome non-dysjunction and increased sensitivity to IR-induced DSBs.
• Revealed synthetic lethality between SYP-1 phosphorylation mutants and *brc-1* mutants, highlighting the interplay between repair pathways.

Conclusions:

• Checkpoint-dependent SYP-1 phosphorylation safeguards the germline against persistent meiotic DSBs.
• This phosphorylation process redirects DNA repair from the homologous chromosome to the sister chromatid.
• The findings provide critical insights into the regulation of meiotic DNA repair and chromosome stability.