WIP1 (wild-type p53-induced phosphatase 1) functions as a homeostatic regulator of the ataxia telangiectasia mutated (ATM)-mediated signaling pathway in response to ionizing radiation (IR). Here we identify homeodomain-interacting protein kinase 2 (HIPK2) as a protein kinase that targets WIP1 for phosphorylation and proteasomal degradation. In unstressed cells, WIP1 is constitutively phosphorylated by HIPK2 and maintained at a low level by proteasomal degradation. In response to IR, ATM-dependent AMPKα2-mediated HIPK2 phosphorylation promotes inhibition of WIP1 phosphorylation through dissociation of WIP1 from HIPK2, followed by stabilization of WIP1 for termination of the ATM-mediated double-strand break (DSB) signaling cascade. Notably, HIPK2 depletion impairs IR-induced γ-H2AX foci formation, cell-cycle checkpoint activation, and DNA repair signaling, and the survival rate of hipk2+/- mice upon γ-irradiation is markedly reduced compared to wild-type mice. Taken together, HIPK2 plays a critical role in the initiation of DSB repair signaling by controlling WIP1 levels in response to IR.
Bibliographical noteFunding Information:
We thank William G. Dunphy, Seok-Geun Lee, Dae-Sik Lim, and Yongsok Kim for commenting on the manuscript. We also thank Kyung-Sup Kim for providing reagents. This work was supported in part by a grant from the National R&D program for Cancer Control, Ministry of Health & Welfare (2011-1120160 to C.Y.C.), the Ubiquitome Research Program (2012-0006126 to C.Y.C.), and the Mid-career Researcher Program through an NRF grant (2009-0085548 to C.Y.C.). We also acknowledge support from the Proteogenomic Research Program (2012M3A9B9036679 to C.L.) funded by the Korean Ministry of Education, Science and Technology.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology