KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

Nature. 2013 Jun 6;498(7452):70-4. doi: 10.1038/nature12201. Epub 2013 May 26.

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

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • 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*
  • Histone Acetyltransferases / metabolism*
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Lysine / chemistry
  • Lysine / metabolism
  • Lysine Acetyltransferase 5
  • Methylation
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphotyrosine / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Tumor Suppressor Proteins
  • Phosphotyrosine
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • Proto-Oncogene Proteins c-abl
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Lysine