WIP1, a Homeostatic Regulator of the DNA Damage Response, Is Targeted by HIPK2 for Phosphorylation and Degradation
- Authors
- Choi, Dong Wook; Na, Wooju; Kabir, Mohammad Humayun; Yi, Eunbi; Kwon, Seonjeong; Yeom, Jeonghun; Ahn, Jang-Won; Choi, Hee-Hyun; Lee, Youngha; Seo, Kyoung Wan; Shin, Min Kyoo; Park, Se-Ho; Yoo, Hae Yong; Isono, Kyo-Ichi; Koseki, Haruhiko; Kim, Seong-Tae; Lee, Cheolju; Kwon, Yunhee Kim; Choi, Cheol Yong
- Issue Date
- 8-Aug-2013
- Publisher
- CELL PRESS
- Citation
- MOLECULAR CELL, v.51, no.3, pp.374 - 385
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR CELL
- Volume
- 51
- Number
- 3
- Start Page
- 374
- End Page
- 385
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/102467
- DOI
- 10.1016/j.molcel.2013.06.010
- ISSN
- 1097-2765
- Abstract
- 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 AMPK alpha 2-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 gamma-H2AX foci formation, cell-cycle checkpoint activation, and DNA repair signaling, and the survival rate of hipk2(+/-) mice upon gamma-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.
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Collections - Graduate School > Department of Life Sciences > 1. Journal Articles
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