title: WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation.
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.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Choi
authors.forename: Wooju
authors.initials: W
authors.lastname: Na
authors.forename: Mohammad Humayun
authors.initials: MH
authors.lastname: Kabir
authors.forename: Eunbi
authors.initials: E
authors.lastname: Yi
authors.forename: Seonjeong
authors.initials: S
authors.lastname: Kwon
authors.forename: Jeonghun
authors.initials: J
authors.lastname: Yeom
authors.forename: Jang-Won
authors.initials: JW
authors.lastname: Ahn
authors.forename: Hee-Hyun
authors.initials: HH
authors.lastname: Choi
authors.forename: Youngha
authors.initials: Y
authors.lastname: Lee
authors.forename: Kyoung Wan
authors.initials: KW
authors.lastname: Seo
authors.forename: Min Kyoo
authors.initials: MK
authors.lastname: Shin
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
authors.forename: Kyo-Ichi
authors.initials: K
authors.lastname: Isono
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.forename: Yunhee Kim
authors.initials: YK
authors.lastname: Kwon
authors.forename: Cheol Yong
authors.initials: CY
authors.lastname: Choi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects*; D004260:DNA Repair; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C468783:H2AX protein, human; D006657:Histones; C115114:HIPK2 protein, human; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C