期刊
NATURE
卷 498, 期 7452, 页码 70-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12201
关键词
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资金
- Cancer Research UK program [C6/A11224]
- European Research Council
- European Community [HEALTH-F2-2010-259893 (DDR)]
- CRUK [C6946/A14492]
- Wellcome Trust [WT092096]
- University of Cambridge, UK
- Herchel Smith Fellowship from the University of Cambridge
- Cancer Research UK [11224] Funding Source: researchfish
The detection of DNA lesions within chromatin represents a critical step in cellular responses to DNA damage. However, the regulatory mechanisms that couple chromatin sensing to DNA-damage signalling in mammalian cells are not well understood. Here we show that tyrosine phosphorylation of the protein acetyltransferase KAT5 (also known as TIP60) increases after DNA damage in a manner that promotes KAT5 binding to the histone mark H3K9me3. This triggers KAT5-mediated acetylation of the ATM kinase, promoting DNA-damage-checkpoint activation and cell survival. We also establish that chromatin alterations can themselves enhance KAT5 tyrosine phosphorylation and ATM-dependent signalling, and identify the proto-oncogene c-Abl as a mediator of this modification. These findings define KAT5 tyrosine phosphorylation as a key event in the sensing of genomic and chromatin perturbations, and highlight a key role for c-Abl in such processes.
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