Antagonistic relationship of NuA4 with the Non-Homologous End-Joining machinery at DNA damage sites

Abstract

The NuA4 histone acetyltransferase complex, apart from its known role in gene regulation, has also been directly implicated in the repair of DNA double-strand breaks (DSBs), favoring homologous recombination (HR) in S/G2 during the cell cycle. Here, we investigate the antagonistic relationship of NuA4 with non-homologous end joining (NHEJ) factors. We detect NuA4 at DSBs in G1 when genes for NHEJ factors Rad9, Yku80 and Nej1 are mutated. This is accompanied with the binding of single-strand DNA binding protein RPA, indicating DNA end resection in G1. This NuA4 recruitment to DSBs depends on both Xrs2 and Lcd1/Ddc2. Introducing an acetyltransferase defective allele in these NHEJ mutant backgrounds decreases their hyper-resection phenotype in G1. Interestingly, we identified two novel non-histone acetylation targets of NuA4, Nej1 and Yku80. Acetyl-mimicking mutant of Nej1 inhibits NHEJ, decreases its interaction with other NHEJ factors and favors resection. Altogether, these results establish an antagonistic regulatory function of NuA4 and NHEJ factors in repair pathway choice and suggest a role of NuA4 in alternative repair mechanism that involves DNA-end resection in G1.