한빛사 논문
Abstract
Dong Wook Choi,1,9 Wooju Na,1,9 Mohammad Humayun Kabir,2 Eunbi Yi,3 Seonjeong Kwon,4 Jeonghun Yeom,2,5 Jang-Won Ahn,1 Hee-Hyun Choi,6 Youngha Lee,7 Kyoung Wan Seo,1 Min Kyoo Shin,1 Se-Ho Park,3 Hae Yong Yoo,7 Kyo-ichi Isono,8 Haruhiko Koseki,8 Seong-Tae Kim,6 Cheolju Lee,2,5 Yunhee Kim Kwon,4 and Cheol Yong Choi1,*
1Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea
2BRI, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea
3School of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea
4Department of Biology and Department of Life and Nanopharmaceutical Science, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu,
Seoul 130-701, Republic of Korea
5Department of Chemical Biology, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea
6Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea
7Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology,
Samsung Medical Center, Sungkyunkwan University, Seoul 135-710, Republic of Korea
8RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan
9These authors contributed equally to this work
*Correspondence: Cheol Yong Choi
Summary
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.
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