Phosphorylation-regulated transitions in an oligomeric state control the activity of the Sae2 DNA repair enzyme.

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  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: United States NLM ID: 8109087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5549 (Electronic) Linking ISSN: 02707306 NLM ISO Abbreviation: Mol Cell Biol Subsets: MEDLINE
    • Publication Information:
      Publication: 2023- : [Philadelphia] : Taylor & Francis
      Original Publication: [Washington, D.C.] : American Society for Microbiology, [c1981-
    • Subject Terms:
      DNA Repair/*genetics ; Endonucleases/*genetics ; Phosphorylation/*genetics ; Saccharomyces cerevisiae Proteins/*genetics; Autophagy/genetics ; Cell Cycle/genetics ; DNA Breaks, Double-Stranded ; Intracellular Signaling Peptides and Proteins/genetics ; Mutation/genetics ; Proteasome Endopeptidase Complex/genetics ; Protein Serine-Threonine Kinases/genetics ; Proteolysis ; Saccharomyces cerevisiae/genetics
    • Abstract:
      In the DNA damage response, many repair and signaling molecules mobilize rapidly at the sites of DNA double-strand breaks. This network of immediate responses is regulated at the level of posttranslational modifications that control the activation of DNA processing enzymes, protein kinases, and scaffold proteins to coordinate DNA repair and checkpoint signaling. Here we investigated the DNA damage-induced oligomeric transitions of the Sae2 protein, an important enzyme in the initiation of DNA double-strand break repair. Sae2 is a target of multiple phosphorylation events, which we identified and characterized in vivo in the budding yeast Saccharomyces cerevisiae. Both cell cycle-dependent and DNA damage-dependent phosphorylation sites in Sae2 are important for the survival of DNA damage, and the cell cycle-regulated modifications are required to prime the damage-dependent events. We found that Sae2 exists in the form of inactive oligomers that are transiently released into smaller active units by this series of phosphorylations. DNA damage also triggers removal of Sae2 through autophagy and proteasomal degradation, ensuring that active Sae2 is present only transiently in cells. Overall, this analysis provides evidence for a novel type of protein regulation where the activity of an enzyme is controlled dynamically by posttranslational modifications that regulate its solubility and oligomeric state.
    • Comments:
      Erratum in: Mol Cell Biol. 2014 Nov 15;34(22):4213.
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    • Grant Information:
      GM67055 United States GM NIGMS NIH HHS; K99 GM088413 United States GM NIGMS NIH HHS; United States HHMI Howard Hughes Medical Institute; R01 GM067055 United States GM NIGMS NIH HHS; GM088413 United States GM NIGMS NIH HHS; R01 CA094008 United States CA NCI NIH HHS; CA094008 United States CA NCI NIH HHS; R00 GM088413 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Intracellular Signaling Peptides and Proteins)
      0 (SAE2 protein, S cerevisiae)
      0 (Saccharomyces cerevisiae Proteins)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.1 (TEL1 protein, S cerevisiae)
      EC 3.1.- (Endonucleases)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • Publication Date:
      Date Created: 20131218 Date Completed: 20140424 Latest Revision: 20211203
    • Publication Date:
      20231215
    • Accession Number:
      PMC4023830
    • Accession Number:
      10.1128/MCB.00963-13
    • Accession Number:
      24344201