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

作者：Bitomsky Nadja; Conrad Elisa; Moritz Christian; Polonio Vallon Tilman; Sombroek Dirk; Schultheiss Kathrin; Glas Carolina; Greiner Vera; Herbel Christoph; Mantovani Fiamma; del Sal Giannino; Peri Francesca; Hofmann Thomas G^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(45): E4203-E4212.

DOI：10.1073/pnas.1310001110

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.

• 出版日期2013-11-5