Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death.
Proc Natl Acad Sci U S A
; 110(45): E4203-12, 2013 Nov 05.
Article
em En
| MEDLINE
| ID: mdl-24145406
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Proteínas de Transporte
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Proteínas Serina-Treonina Quinases
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Apoptose
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Peptidilprolil Isomerase
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Ativação Enzimática
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article