Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

• Verfasst von: Bitomsky, Nadja [VerfasserIn]
• Verfasst von: Conrad, Elisa [VerfasserIn]
• Verfasst von: Moritz, Christian [VerfasserIn]
• Verfasst von: Polonio-Vallon, Tilman [VerfasserIn]
• Verfasst von: Sombroek, Dirk [VerfasserIn]
• Verfasst von: Schultheiß, Kathrin [VerfasserIn]
• Verfasst von: Glas, Carolina [VerfasserIn]
• Verfasst von: Greiner, Vera [VerfasserIn]
• Verfasst von: Herbel, Christoph [VerfasserIn]
• Verfasst von: Mantovani, Fiamma [VerfasserIn]
• Verfasst von: Sal, Giannino del [VerfasserIn]
• Verfasst von: Peri, Francesca [VerfasserIn]
• Verfasst von: Hofmann, Thomas G. [VerfasserIn]
• Titel: Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death
• Verf.angabe: Nadja Bitomsky, Elisa Conrad, Christian Moritz, Tilman Polonio-Vallon, Dirk Sombroek, Kathrin Schultheiss, Carolina Glas, Vera Greiner, Christoph Herbel, Fiamma Mantovani, Giannino del Sal, Francesca Peri, and Thomas G. Hofmann
• E-Jahr: 2013
• Jahr: October 21, 2013
• Umfang: 10 S.
• Fussnoten: Gesehen am 26.11.2020
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2013
• Band/Heft Quelle: 110(2013), 45, Seite E4203-E4212
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1310001110
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1741205328

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.