TY - JOUR
T1 - A novel role for greatwall kinase in recovery from DNA damage
AU - Peng, Aimin
AU - Yamamoto, Tomomi M.
AU - Goldberg, Michael L.
AU - Maller, James L.
N1 - Funding Information:
This work was supported by the Howard Hughes Medical Institute and by a grant from the NIH to M.L.G. (GM48430). A.P. and T.M.M. are Research Associates and J.L.M. an Investigator of the Howard Hughes Medical Institute.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression. The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G2/M transition and helps maintain M phase through inhibition of PP 2A/B55δ, the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl overexpression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA damage.
AB - Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression. The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G2/M transition and helps maintain M phase through inhibition of PP 2A/B55δ, the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl overexpression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA damage.
KW - Checkpoint recovery
KW - DNA damage
KW - Greatwall
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U2 - 10.4161/cc.9.21.13632
DO - 10.4161/cc.9.21.13632
M3 - Article
C2 - 20980823
AN - SCOPUS:78349301924
SN - 1538-4101
VL - 9
SP - 4364
EP - 4369
JO - Cell Cycle
JF - Cell Cycle
IS - 21
ER -