HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism
| Autor: | M. Liebl, Thomas G. Hofmann, M. Meister, S. Schumacher, Christoph Herbel, Sonja Matt, Eva Krieghoff-Henning, V. Greiner, Nadja Bitomsky, E. Conrad, B. Kriznik, Tilman Polonio-Vallon |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Programmed cell death endocrine system diseases DNA repair DNA damage Apoptosis Protein Serine-Threonine Kinases Biology environment and public health 03 medical and health sciences chemistry.chemical_compound Leukemia Promyelocytic Acute Sirtuin 1 Cell Line Tumor Humans Phosphorylation Molecular Biology Original Paper Cell growth Kinase Acetylation Cell Biology Gene Expression Regulation Neoplastic enzymes and coenzymes (carbohydrates) 030104 developmental biology chemistry Cancer research biology.protein Tumor Suppressor Protein p53 biological phenomena cell phenomena and immunity Carrier Proteins hormones hormone substitutes and hormone antagonists DNA DNA Damage Protein Binding |
| Zdroj: | Cell Death and Differentiation |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/cdd.2015.75 |
| Popis: | Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response. |
| Databáze: | OpenAIRE |
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