title: Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response.
abstract: The integrity of DNA is constantly challenged throughout the life of a cell by both endogenous and exogenous stresses. A well-organized rapid damage response and proficient DNA repair, therefore, become critically important for maintaining genomic stability and cell survival. When DNA is damaged, the DNA damage response (DDR) can be initiated by alterations in chromosomal structure and histone modifications, such as the phosphorylation of the histone H2AX (the phosphorylated form is referred to as gamma-H2AX). gamma-H2AX plays a crucial role in recruiting DDR factors to damage sites for accurate DNA repair. On repair completion, gamma-H2AX must then be reverted to H2AX by dephosphorylation for attenuation of the DDR. Here, we report that the wild-type p53-induced phosphatase 1 (Wip1) phosphatase, which is often overexpressed in a variety of tumors, effectively dephosphorylates gamma-H2AX in vitro and in vivo. Ectopic expression of Wip1 significantly reduces the level of gamma-H2AX after ionizing as well as UV radiation. Forced premature dephosphorylation of gamma-H2AX by Wip1 disrupts recruitment of important DNA repair factors to damaged sites and delays DNA damage repair. Additionally, deletion of Wip1 enhances gamma-H2AX levels in cells undergoing constitutive oncogenic stress. Taken together, our studies show that Wip1 is an important mammalian phosphatase for gamma-H2AX and shows an additional mechanism for Wip1 in the tumor surveillance network.
authors.affiliation: Department of Biochemistry, Georgetown University, Washington, District of Columbia 20057-1468, USA. hjcha@cha.ac.kr
authors.forename: Hyukjin
authors.initials: H
authors.lastname: Cha
authors.forename: Julie M
authors.initials: JM
authors.lastname: Lowe
authors.forename: Henghong
authors.initials: H
authors.lastname: Li
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Galina I
authors.initials: GI
authors.lastname: Belova
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bulavin
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007259:Infrared Rays; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays; D014965:X-Rays
chemical_list: C468783:H2AX protein, human; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C
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