Distinct phosphatases antagonize the p53 response in different phases of the cell cycle.
The basic machinery that detects DNA damage is the same throughout the cell cycle. Here, we show, in contrast, that reversal of DNA damage responses (DDRs) and recovery are fundamentally different in G1 and G2 phases of the cell cycle. We find that distinct phosphatases are required to counteract the checkpoint response in G1 vs. G2. Whereas WT p53-induced phosphatase 1 (Wip1) promotes recovery in G2-arrested cells by antagonizing p53, it is dispensable for recovery from a G1 arrest. Instead, we identify phosphoprotein phosphatase 4 catalytic subunit (PP4) to be specifically required for cell cycle restart after DNA damage in G1. PP4 dephosphorylates Krüppel-associated box domain-associated protein 1-S473 to repress p53-dependent transcriptional activation of p21 when the DDR is silenced. Taken together, our results show that PP4 and Wip1 are differentially required to counteract the p53-dependent cell cycle arrest in G1 and G2, by antagonizing early or late p53-mediated responses, respectively.
Divisions of Cell Biology and.
Indra A
IA
Shaltiel
Divisions of Cell Biology and.
Melinda
M
Aprelia
Division of Cancer Research, University of Dundee, Dundee DD1 9SY, United Kingdom;
Adrian T
AT
Saurin
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215;
Dipanjan
D
Chowdhury
Cancer Genomics Center, 3584 CG, Utrecht, The Netherlands; andDepartment of Biomedical Genetics, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Geert J P L
GJ
Kops
Cancer Genomics Center, 3584 CG, Utrecht, The Netherlands; andMolecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
Emile E
EE
Voest
Divisions of Cell Biology andCancer Genomics Center, 3584 CG, Utrecht, The Netherlands; and r.medema@nki.nl.
René H
RH
Medema
D002453:Cell Cycle; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase / Q000528:radiation effects; D016195:G2 Phase / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D017434:Protein Structure, Tertiary; D055213:Retinal Pigment Epithelium / Q000166:cytology; D019098:Telomerase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C534699:CCNB1 protein, human; D056744:Cyclin B1; D008164:Luminescent Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C080406:protein phosphatase 4