A novel role for greatwall kinase in recovery from DNA damage.
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 G(2)/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.
Peng
Aimin
A
Howard Hughes Medical Institute, Department of Pharmacology, University of Colorado School of Medicine, Aurora, USA. Aimin.Peng@unmc.edu
Yamamoto
Tomomi M
TM
Goldberg
Michael L
ML
Maller
James L
JL
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002455:Cell Division; D004249:DNA Damage; D004260:DNA Repair; D016195:G2 Phase; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014982:Xenopus laevis
D029867:Xenopus Proteins; C544010:MASTL protein, Xenopus; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1