title: Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death.
abstract: Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis.
authors.affiliation: German Cancer Research Center, Cellular Senescence Group, Deutsches Krebsforschungszentrum-Zentrum für Molekulare Biologie der Universität Heidelberg Alliance (DKFZ-ZMBH), 69120 Heidelberg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bitomsky
authors.forename: Elisa
authors.initials: E
authors.lastname: Conrad
authors.forename: Christian
authors.initials: C
authors.lastname: Moritz
authors.forename: Tilman
authors.initials: T
authors.lastname: Polonio-Vallon
authors.forename: Dirk
authors.initials: D
authors.lastname: Sombroek
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schultheiss
authors.forename: Carolina
authors.initials: C
authors.lastname: Glas
authors.forename: Vera
authors.initials: V
authors.lastname: Greiner
authors.forename: Christoph
authors.initials: C
authors.lastname: Herbel
authors.forename: Fiamma
authors.initials: F
authors.lastname: Mantovani
authors.forename: Giannino
authors.initials: G
authors.lastname: del Sal
authors.forename: Francesca
authors.initials: F
authors.lastname: Peri
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D008856:Microscopy, Fluorescence; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase