Phospho-dependent recruitment of the yeast NuA4 acetyltransferase complex by MRX at DNA breaks regulates RPA dynamics during resection

Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10028-10033. doi: 10.1073/pnas.1806513115. Epub 2018 Sep 17.


The KAT5 (Tip60/Esa1) histone acetyltransferase is part of NuA4, a large multifunctional complex highly conserved from yeast to mammals that targets lysines on H4 and H2A (X/Z) tails for acetylation. It is essential for cell viability, being a key regulator of gene expression, cell proliferation, and stem cell renewal and an important factor for genome stability. The NuA4 complex is directly recruited near DNA double-strand breaks (DSBs) to facilitate repair, in part through local chromatin modification and interplay with 53BP1 during the DNA damage response. While NuA4 is detected early after appearance of the lesion, its precise mechanism of recruitment remains to be defined. Here, we report a stepwise recruitment of yeast NuA4 to DSBs first by a DNA damage-induced phosphorylation-dependent interaction with the Xrs2 subunit of the Mre11-Rad50-Xrs2 (MRX) complex bound to DNA ends. This is followed by a DNA resection-dependent spreading of NuA4 on each side of the break along with the ssDNA-binding replication protein A (RPA). Finally, we show that NuA4 can acetylate RPA and regulate the dynamics of its binding to DNA, hence targeting locally both histone and nonhistone proteins for lysine acetylation to coordinate repair.

Keywords: DNA double-strand break; NuA4; RPA; chromatin; lysine acetylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • DNA Breaks, Double-Stranded*
  • DNA, Fungal* / chemistry
  • DNA, Fungal* / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Endodeoxyribonucleases / chemistry
  • Endodeoxyribonucleases / metabolism
  • Exodeoxyribonucleases / chemistry
  • Exodeoxyribonucleases / metabolism
  • Histone Acetyltransferases* / chemistry
  • Histone Acetyltransferases* / metabolism
  • Saccharomyces cerevisiae Proteins* / chemistry
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / chemistry
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • DNA, Fungal
  • DNA-Binding Proteins
  • RAD50 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • XRS2 protein, S cerevisiae
  • Histone Acetyltransferases
  • NuA4 protein, S cerevisiae
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases
  • MRE11 protein, S cerevisiae