ZFIN ID: ZDB-PUB-131119-38
Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death
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.
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.