Publication Date:
2013-05-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859897/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859897/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaidi, Abderrahmane -- Jackson, Stephen P -- 092096/Wellcome Trust/United Kingdom -- 11224/Cancer Research UK/United Kingdom -- 268536/European Research Council/International -- A11224/Cancer Research UK/United Kingdom -- C6/A11224/Cancer Research UK/United Kingdom -- WT092096/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Jun 6;498(7452):70-4. doi: 10.1038/nature12201. Epub 2013 May 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708966" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Ataxia Telangiectasia Mutated Proteins
;
Cell Cycle Checkpoints
;
Cell Cycle Proteins/*metabolism
;
Cell Line
;
Cell Survival/radiation effects
;
Chromatin/*metabolism
;
DNA Damage
;
DNA-Binding Proteins/*metabolism
;
Enzyme Activation
;
HeLa Cells
;
Histone Acetyltransferases/*chemistry/*metabolism
;
Histones/chemistry/metabolism
;
Humans
;
Lysine/chemistry/metabolism
;
Methylation
;
Molecular Sequence Data
;
Phosphorylation
;
Phosphotyrosine/*metabolism
;
Protein-Serine-Threonine Kinases/*metabolism
;
Proto-Oncogene Proteins c-abl/metabolism
;
*Signal Transduction
;
Tumor Suppressor Proteins/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
