First Author | Bitomsky N | Year | 2013 |
Journal | Proc Natl Acad Sci U S A | Volume | 110 |
Issue | 45 | Pages | E4203-12 |
PubMed ID | 24145406 | Mgi Jnum | J:202918 |
Mgi Id | MGI:5523374 | Doi | 10.1073/pnas.1310001110 |
Citation | Bitomsky N, et al. (2013) Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci U S A 110(45):E4203-12 |
abstractText | 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. |