Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Amino Acid Sequence
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Checkpoints
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cell Survival / radiation effects
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Chromatin / metabolism*
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DNA Damage
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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HeLa Cells
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Histone Acetyltransferases / chemistry*
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Histone Acetyltransferases / metabolism*
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Histones / chemistry
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Histones / metabolism
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Humans
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Lysine / chemistry
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Lysine / metabolism
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Lysine Acetyltransferase 5
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Methylation
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Molecular Sequence Data
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Phosphorylation
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Phosphotyrosine / metabolism*
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-abl / metabolism
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Signal Transduction*
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Tumor Suppressor Proteins / metabolism*
Substances
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Cell Cycle Proteins
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Chromatin
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DNA-Binding Proteins
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Histones
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MAS1 protein, human
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Proto-Oncogene Mas
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Tumor Suppressor Proteins
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Phosphotyrosine
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5
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Proto-Oncogene Proteins c-abl
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Lysine