The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair.
Nucleotide excision repair (NER) is the only mechanism in humans to repair UV-induced DNA lesions such as pyrimidine (6-4) pyrimidone photoproducts and cyclobutane pyrimidine dimers (CPDs). In response to UV damage, the ataxia telangiectasia mutated and Rad3-related (ATR) kinase phosphorylates and activates several downstream effector proteins, such as p53 and XPA, to arrest cell cycle progression, stimulate DNA repair, or initiate apoptosis. However, following the completion of DNA repair, there must be active mechanisms that restore the cell to a prestressed homeostatic state. An important part of this recovery must include a process to reduce p53 and NER activity as well as to remove repair protein complexes from the DNA damage sites. Since activation of the damage response occurs in part through phosphorylation, phosphatases are obvious candidates as homeostatic regulators of the DNA damage and repair responses. Therefore, we investigated whether the serine/threonine wild-type p53-induced phosphatase 1 (WIP1/PPM1D) might regulate NER. WIP1 overexpression inhibits the kinetics of NER and CPD repair, whereas WIP1 depletion enhances NER kinetics and CPD repair. This NER suppression is dependent on WIP1 phosphatase activity, as phosphatase-dead WIP1 mutants failed to inhibit NER. Moreover, WIP1 suppresses the kinetics of UV-induced damage repair largely through effects on NER, as XPD-deficient cells are not further suppressed in repairing UV damage by overexpressed WIP1. Wip1 null mice quickly repair their CPD and undergo less UV-induced apoptosis than their wild-type counterparts. In vitro phosphatase assays identify XPA and XPC as two potential WIP1 targets in the NER pathway. Thus WIP1 may suppress NER kinetics by dephosphorylating and inactivating XPA and XPC and other NER proteins and regulators after UV-induced DNA damage is repaired.
Nguyen
Thuy-Ai
TA
Baylor College of Medicine, Houston, TX 77030, United States. thuyaitn@yahoo.com <thuyaitn@yahoo.com>
Slattery
Scott D
SD
Moon
Sung-Hwan
SH
Darlington
Yolanda F
YF
Lu
Xiongbin
X
Donehower
Lawrence A
LA
D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology*; D000071636:Protein Phosphatase 2C; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C501002:Xpc protein, mouse; D004247:DNA; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C
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