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 2024-01-20T11:34:57Z 2024-01-20T11:34:57Z 2021-09-04 2013-08-08 1097-2765 https://pubs.kist.re.kr/handle/201004/127777 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. English CELL PRESS HOMEODOMAIN-INTERACTING PROTEIN-KINASE-2 IONIZING-RADIATION TRANSCRIPTION FACTORS SIGNALING PATHWAY PROTEIN-KINASES CANCER-CELLS PHOSPHATASE ATM AMPK P53 WIP1, a Homeostatic Regulator of the DNA Damage Response, Is Targeted by HIPK2 for Phosphorylation and Degradation Article 10.1016/j.molcel.2013.06.010 1 MOLECULAR CELL, v.51, no.3, pp.374 - 385 MOLECULAR CELL 51 3 374 385 scie scopus 000323086400012 2-s2.0-84881558218 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article HOMEODOMAIN-INTERACTING PROTEIN-KINASE-2 IONIZING-RADIATION TRANSCRIPTION FACTORS SIGNALING PATHWAY PROTEIN-KINASES CANCER-CELLS PHOSPHATASE ATM AMPK P53