WIP1, a Homeostatic Regulator of the DNA Damage Response, Is Targeted by HIPK2 for Phosphorylation and Degradation

DongWook Choi, Wooju Na, MohammadHumayun Kabir, Eunbi Yi, Seonjeong Kwon, Jeonghun Yeom, Jang Won Ahn, Hee Hyun Choi, Youngha Lee, KyoungWan Seo, MinKyoo Shin, Se-Ho Park, HaeYong Yoo, Kyo ichi Isono, Haruhiko Koseki, Seong Tae Kim, Cheolju Lee, YunheeKim Kwon, CheolYong Choi

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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 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.

Original languageEnglish
Pages (from-to)374-385
Number of pages12
JournalMolecular Cell
Volume51
Issue number3
DOIs
Publication statusPublished - 2013 Aug 8

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Choi, D., Na, W., Kabir, M., Yi, E., Kwon, S., Yeom, J., Ahn, J. W., Choi, H. H., Lee, Y., Seo, K., Shin, M., Park, S-H., Yoo, H., Isono, K. I., Koseki, H., Kim, S. T., Lee, C., Kwon, Y., & Choi, C. (2013). WIP1, a Homeostatic Regulator of the DNA Damage Response, Is Targeted by HIPK2 for Phosphorylation and Degradation. Molecular Cell, 51(3), 374-385. https://doi.org/10.1016/j.molcel.2013.06.010