Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death
- Authors
- Bitomsky, N., Conrad, E., Moritz, C., Polonio-Vallon, T., Sombroek, D., Schultheiss, K., Glas, C., Greiner, V., Herbel, C., Mantovani, F., Del Sal, G., Peri, F., and Hofmann, T.G.
- ID
- ZDB-PUB-131119-38
- Date
- 2013
- Source
- Proceedings of the National Academy of Sciences of the United States of America 110(45): E4203-4212 (Journal)
- Registered Authors
- Peri, Francesca
- Keywords
- none
- MeSH Terms
-
- Apoptosis/physiology*
- Carrier Proteins/metabolism*
- Cell Line
- DNA Damage/physiology*
- Enzyme Activation/physiology*
- Genetic Vectors
- Humans
- Microscopy, Fluorescence
- Peptidylprolyl Isomerase/metabolism*
- Phosphorylation
- Protein Serine-Threonine Kinases/metabolism*
- RNA Interference
- RNA, Small Interfering/genetics
- PubMed
- 24145406 Full text @ Proc. Natl. Acad. Sci. USA
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.