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Cell cycle-dependent regulation of the nuclease activity of Mus81-Eme1/Mms4

María Gallo-Fernández1, Irene Saugar, María Ángeles Ortiz-Bazán

  • 1Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, 28049 Madrid, Spain.

Nucleic Acids Research
|June 26, 2012
PubMed

Insights

Budding yeast Mus81-Mms4 nuclease activity is regulated by phosphorylation during the cell cycle. This ensures its function in resolving DNA replication stress only after DNA synthesis, maintaining genomic integrity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The Mus81-Eme1/Mms4 endonuclease is crucial for maintaining genomic integrity in eukaryotes.
  • Its precise regulation is essential to prevent detrimental effects on genome stability.

Purpose of the Study:

  • To investigate the cell cycle regulation of the budding yeast Mus81-Mms4 complex.
  • To elucidate the role of Mms4 phosphorylation in controlling nuclease activity.

Main Methods:

  • Analysis of Mus81-Mms4 complex activity in budding yeast.
  • Investigating the effects of phosphorylation-defective mutants on DNA damage sensitivity.
  • Utilizing cell cycle synchronization and biochemical assays.

Main Results:

  • Budding yeast Mus81-Mms4 is regulated by phosphorylation of Mms4, dependent on Cdc28 (CDK) and Cdc5 (Polo-like kinase).
  • Phosphorylation occurs post-DNA synthesis and pre-chromosome segregation, and is vital for complex function.
  • A phosphorylation-defective mms4 mutant exhibits reduced nuclease activity and increased sensitivity to DNA damaging agents, especially in Sgs1-deficient cells.

Conclusions:

  • Cell cycle-specific phosphorylation of Mms4 restricts Mus81-Mms4 activity to a critical window, preventing genome instability during replication.
  • Controlled Mus81-Mms4 activity acts as a safeguard to resolve post-replication DNA structures before mitosis.

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