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

Xue Cheng, Olivier Jobin-Robitaille, Pierre Billon, Rémi Buisson, Hengyao Niu, Nicolas Lacoste, Nebiyu Abshiru, Valérie Côté, Pierre Thibault, Stephen J. Kron, Patrick Sung, Christopher J. Brandl, Jean Yves Masson, Jacques Côté

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10028-10033
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number40
DOIs
StatePublished - Oct 2 2018
Externally publishedYes

Keywords

  • Chromatin
  • DNA double-strand break
  • Lysine acetylation
  • NuA4
  • RPA

ASJC Scopus subject areas

  • General

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