Regulation of Chk2 Ubiquitination and Signaling through Autophosphorylation of Serine 379
- 1 October 2008
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 28 (19), 5874-5885
- https://doi.org/10.1128/mcb.00821-08
Abstract
The Chk2 protein kinase protects genome integrity by promoting cell cycle arrest or apoptosis in response to DNA double-strand breaks, and Chk2 mutations are found in both familial and sporadic cancers. Exposure of cells to ionizing radiation (IR) or radiomimetic drugs induces Chk2 phosphorylation by ATM, followed by Chk2 oligomerization, auto-/transphosphorylation, and activation. Here we demonstrate that Chk2 is ubiquitinated upon activation and that this requires Chk2 kinase activity. Serine 379 (S379) was identified as a novel IR-inducible autophosphorylation site required for ubiquitination of Chk2 by a Cullin 1-containing E3 ligase complex. Importantly, S379 was required for Chk2 to induce apoptosis in cells with DNA double-strand breaks. Thus, auto-/transphosphorylation of S379 is required for Chk2 ubiquitination and effector function.Keywords
This publication has 57 references indexed in Scilit:
- Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damageProceedings of the National Academy of Sciences of the United States of America, 2007
- Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin LigaseScience, 2007
- RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein AssemblyCell, 2007
- RNF8 Ubiquitylates Histones at DNA Double-Strand Breaks and Promotes Assembly of Repair ProteinsCell, 2007
- Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage ResponseScience, 2007
- Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA DamageMolecular and Cellular Biology, 2006
- ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damageThe EMBO Journal, 2005
- Function and regulation of cullin–RING ubiquitin ligasesNature Reviews Molecular Cell Biology, 2005
- MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathwaysNature, 2003
- Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complexNature, 2002