Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks

Nat Cell Biol. 2006 Jan;8(1):91-9. doi: 10.1038/ncb1343. Epub 2005 Dec 11.

Abstract

DNA is packaged into chromatin, a highly compacted DNA-protein complex; therefore, all cellular processes that use the DNA as a template, including DNA repair, require a high degree of coordination between the DNA-repair machinery and chromatin modification/remodelling, which regulates the accessibility of DNA in chromatin. Recent studies have implicated histone acetyltransferase (HAT) complexes and chromatin acetylation in DNA repair; however, the precise underlying mechanism remains poorly understood. Here, we show that the HAT cofactor Trrap and Tip60 HAT bind to the chromatin surrounding sites of DNA double-strand breaks (DSBs) in vivo. Trrap depletion impairs both DNA-damage-induced histone H4 hyperacetylation and accumulation of repair molecules at sites of DSBs, resulting in defective homologous recombination (HR) repair, albeit with the presence of a functional ATM-dependent DNA-damage signalling cascade. Importantly, the impaired loading of repair proteins and the defect in DNA repair in Trrap-deficient cells can be counteracted by chromatin relaxation, indicating that the DNA-repair defect that was observed in the absence of Trrap is due to impeded chromatin accessibility at sites of DNA breaks. Thus, these data reveal that cells may use the same basic mechanism involving HAT complexes to regulate distinct cellular processes, such as transcription and DNA repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cells, Cultured
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • DNA Damage
  • DNA Repair / drug effects*
  • Deoxyribonucleases, Type II Site-Specific / genetics
  • Deoxyribonucleases, Type II Site-Specific / metabolism
  • Electroporation
  • HeLa Cells
  • Histone Acetyltransferases / metabolism*
  • Histones / metabolism
  • Humans
  • Lysine Acetyltransferase 5
  • Male
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Small Interfering
  • Recombination, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saccharomyces cerevisiae Proteins
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Chromatin
  • Histones
  • Nuclear Proteins
  • RNA, Small Interfering
  • Saccharomyces cerevisiae Proteins
  • transformation-transcription domain-associated protein
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • SCEI protein, S cerevisiae
  • Deoxyribonucleases, Type II Site-Specific