CDK and Mec1/Tel1-catalyzed phosphorylation of Sae2 regulate different responses to DNA damage.

Sae2 functions in the DNA damage response by controlling Mre11-Rad50-Xrs2 (MRX)-catalyzed end resection, an essential step for homology-dependent repair of double-strand breaks (DSBs), and by attenuating DNA damage checkpoint signaling. Phosphorylation of Sae2 by cyclin-dependent kinase (CDK1/Cdc28) activates the Mre11 endonuclease, while the physiological role of Sae2 phosphorylation by Mec1 ...
and Tel1 checkpoint kinases is not fully understood. Here, we compare the phenotype of sae2 mutants lacking the main CDK (sae2-S267A) or Mec1 and Tel1 phosphorylation sites (sae2-5A) with sae2? and Mre11 nuclease defective (mre11-nd) mutants. The phosphorylation-site mutations confer DNA damage sensitivity, but not to the same extent as sae2?. The sae2-S267A mutation is epistatic to mre11-nd for camptothecin (CPT) sensitivity and synergizes with sgs1?, whereas sae2-5A synergizes with mre11-nd and exhibits epistasis with sgs1?. We find that attenuation of checkpoint signaling by Sae2 is mostly independent of Mre11 endonuclease activation but requires Mec1 and Tel1-dependent phosphorylation of Sae2. These results support a model whereby CDK-catalyzed phosphorylation of Sae2 activates resection via Mre11 endonuclease, whereas Sae2 phosphorylation by Mec1 and Tel1 promotes resection by the Dna2-Sgs1 and Exo1 pathways indirectly by dampening the DNA damage response.
Mesh Terms:
Catalysis, Cyclin-Dependent Kinases, DNA Breaks, Double-Stranded, DNA Damage, DNA Helicases, Endonucleases, Exodeoxyribonucleases, Intracellular Signaling Peptides and Proteins, Organisms, Genetically Modified, Phosphorylation, Protein-Serine-Threonine Kinases, RecQ Helicases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction
Nucleic Acids Res.
Date: Dec. 02, 2018
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