Wip1 Directly Dephosphorylates γ-H2AX and Attenuates the DNA Damage Response

Department of Biochemistry, Georgetown University, Washington, District of Columbia 20057-1468, USA.
Cancer Research (Impact Factor: 9.33). 05/2010; 70(10):4112-22. DOI: 10.1158/0008-5472.CAN-09-4244
Source: PubMed


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.

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Available from: Hyuk-Jin Cha
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    • "More recently, PPM1D/WIP1 was shown to interact with γ-H2AX and to mediate a delayed γ-H2AX dephosphorylation after DNA damage to promote the resolution of the DNA damage foci (50,51). The premature dephosphorylation of γ-H2AX after DNA damage by WIP1 expression also results in failure to recruit DNA repair molecules to DNA damage foci and attenuates the DNA damage response (52). PPM1D/WIP1 also maintains cellular competence to divide during an ongoing DNA damage response in G2 (53). "
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    • "Wip1 A recent study reported that Wip1 binds directly to H2AX and dephosphorylates it in vitro and in vivo, leading to reverse checkpoint signaling (Cha et al., 2010; Figure 1F). Moreover, ectopic expression of Wip1 reduces IR-induced γ-H2AX and foci formation for several DDR factors, leading to delayed DNA repair after IR. "
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    • "Wip1 is encoded by PPM1D (for protein phosphatase 1D Mg 2þ dependent , delta isoform) and is a type 2C protein phosphatase (PP2C). A number of stress mediators such as p53 [19], p38 [20], Chk1/2 [21], ATM [22] and g-H2AX [23] [24] are dephosphorylated and inactivated by Wip1. Through inactivation of stress mediators, Wip1 can modulate stress responses such as growth arrest or cellular senescence under conditions of stress [24]. "
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