TY - JOUR
T1 - Deregulated Ras signaling compromises DNA damage checkpoint recovery in S. cerevisiae
AU - Wood, Matthew D.
AU - Sanchez, Yolanda
N1 - Funding Information:
We thank members of the Sanchez Laboratory for their insightful comments on this work and Deborah Hogan for comments on the manuscript. This work was funded by NIH/NCI R01CA84463 and NIH/NINDS R21NS060940 to YS (http:// www.cancer.gov/, http://www.ninds.nih.gov/), NIH training grant T32-CA009658-18 (http://www.nih.gov/) and by a Children’s Tumor Foundation Young Investigator Award to M.D.W. (http://www.ctf.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.D.W. is an Albert J. Ryan fellow. The authors declare no competing financial interests.
PY - 2010/8/15
Y1 - 2010/8/15
N2 - 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.
AB - 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.
KW - Anaphase promoting complex
KW - Budding yeast
KW - Camp-dependent protein kinase
KW - Dna damage checkpoint
KW - Neurofibromatosis type 1
KW - Ras signaling
UR - http://www.scopus.com/inward/record.url?scp=77955720762&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955720762&partnerID=8YFLogxK
U2 - 10.4161/cc.9.16.12713
DO - 10.4161/cc.9.16.12713
M3 - Article
C2 - 20716966
AN - SCOPUS:77955720762
SN - 1538-4101
VL - 9
SP - 3373
EP - 3383
JO - Cell Cycle
JF - Cell Cycle
IS - 16
ER -