Deregulated Ras signaling compromises DNA damage checkpoint recovery in S. cerevisiae

Matthew D. Wood, Yolanda Sanchez

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The DNA damage checkpoint maintains genome stability by arresting the cell cycle and promoting DNA repair under genotoxic stress. Cells must downregulate the checkpoint signaling pathways in order to resume cell division after completing DNA repair. While the mechanisms of checkpoint activation have been well-characterized, the process of checkpoint recovery, and the signals regulating it, has only recently been investigated. We have identified a new role for the Ras signaling pathway as a regulator of DNA damage checkpoint recovery. Here we report that in budding yeast, deletion of the IRA1 and IRA2 genes encoding negative regulators of Ras prevents cellular recovery from a DNA damage induced arrest. The checkpoint kinase Rad53 is dephosphorylated in an IRA-deficient strain, indicating that recovery failure is not caused by constitutive checkpoint pathway activation. The ira1Δ ira2Δ recovery defect requires the checkpoint kinase Chk1 and the cAMP-dependent protein kinase (PKA) catalytic subunit Tpk2. Furthermore, PKA phosphorylation sites on the anaphase promoting complex specificity factor Cdc20 are required for the recovery defect, indicating a link between the recovery defect and PKA regulation of mitosis. This work identifies a new signaling pathway that can regulate DNA damage checkpoint recovery and implicates the Ras signaling pathway as an important regulator of mitotic events.

Original languageEnglish (US)
Pages (from-to)3373-3383
Number of pages11
JournalCell Cycle
Volume9
Issue number16
DOIs
StatePublished - Aug 15 2010

Keywords

  • Anaphase promoting complex
  • Budding yeast
  • Camp-dependent protein kinase
  • Dna damage checkpoint
  • Neurofibromatosis type 1
  • Ras signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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