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DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage.
- Source :
-
Journal of molecular cell biology [J Mol Cell Biol] 2012 Oct; Vol. 4 (5), pp. 294-303. Date of Electronic Publication: 2012 Jun 26. - Publication Year :
- 2012
-
Abstract
- Human DBC1 (deleted in breast cancer-1; KIAA1967) is a nuclear protein that, in response to DNA damage, competitively inhibits the NAD(+)-dependent deacetylase SIRT1, a regulator of p53 apoptotic functions in response to genotoxic stress. DBC1 depletion in human cells increases SIRT1 activity, resulting in the deacetylation of p53 and protection from apoptosis. However, the mechanisms regulating this process have not yet been determined. Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. Indeed, DBC1-mediated genotoxicity, which was shown in knockdown experiments to be dependent on SIRT1 and p53 expression, was defective in cells expressing the phospho-mutant DBC1(T454A). This study describes the first post-translational modification of DBC1 and provides new mechanistic insight linking ATM/ATR to the DBC1-SIRT1-p53 apoptotic axis triggered by DNA damage.
- Subjects :
- Acetylation
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins genetics
Cell Line, Tumor
HEK293 Cells
Humans
Phosphorylation
Protein Serine-Threonine Kinases genetics
Sirtuin 1 genetics
Sirtuin 1 metabolism
Adaptor Proteins, Signal Transducing metabolism
Cell Cycle Proteins metabolism
DNA Damage physiology
DNA-Binding Proteins metabolism
Protein Serine-Threonine Kinases metabolism
Sirtuin 1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1759-4685
- Volume :
- 4
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of molecular cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 22735644
- Full Text :
- https://doi.org/10.1093/jmcb/mjs035