Schizosaccharomyces pombeKAT5 contributes to resection and repair of a DNA double strand break

Abstract

10Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, 11 human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates 12 various DNA damage response activities at a DSB, including histone remodeling and activation of the DNA 13 damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show 14 that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. 15These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair 16 by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of 17 histone variant H2A.Z, which has been proposed to affect resection. These data suggest that Mst1 functions to 18 direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand 19 break. 20 21 the most highly conserved HAT of this family, known as Mst1 in S. pombe, Esa1 in S. cerevisiae, and TIP60 in 34 mammals (reviewed in (Avvakumov and Côté 2007; Pillus 2008)). The gene is essential for viability in all species, 35 because in addition to its role in DSB repair it performs other functions such as transcriptional regulation, 36 heterochromatin assembly and centromere assembly (Doyon and Côté 2004; Ghobashi and Kamel 2018; Gómez 37 et al. 2008; Nugent et al. 2010; Pillus 2008). In humans, TIP60 has also been identified as a tumor suppressor 38 (rev. (Sapountzi, Logan, and Robson 2006; Voss and Thomas 2009) and is a therapeutic target (rev. in (Judes et 39 al. 2015). 40 KAT5 contains a chromodomain in addition to its HAT domain, which suggests that it binds methylated 41 histones (rev. in (De La Cruz et al. 2005; Utley and Côté 2003)). KAT5 functions in the context of a large protein 42 complex called NuA4, and acetylates numerous substrates including histones H2A, H3, and H4, and the histone 43