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Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Nov 05; Vol. 110 (45), pp. E4203-12. Date of Electronic Publication: 2013 Oct 21. - Publication Year :
- 2013
-
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.
- Subjects :
- Cell Line
Genetic Vectors
Humans
Microscopy, Fluorescence
NIMA-Interacting Peptidylprolyl Isomerase
Phosphorylation
RNA Interference
RNA, Small Interfering genetics
Apoptosis physiology
Carrier Proteins metabolism
DNA Damage physiology
Enzyme Activation physiology
Peptidylprolyl Isomerase metabolism
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 24145406
- Full Text :
- https://doi.org/10.1073/pnas.1310001110