Program of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089-2910, USA.
Department of Molecular Genetics, Ohio State University, Marion, OH 43302, USA.
Genetics. 2021 May 17;218(1). doi: 10.1093/genetics/iyab042.
Chromatin remodeling is essential for effective repair of a DNA double-strand break (DSB). KAT5 (Schizosaccharomyces pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DNA DSB, including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination (HR). These phenotypes of mst1 are similar to pht1-4KR, a nonacetylatable form of histone variant H2A.Z, which has been proposed to affect resection. Our data suggest that Mst1 functions to direct repair of DSBs toward HR pathways by modulating resection at the DSB.
染色质重塑对于有效修复 DNA 双链断裂 (DSB) 至关重要。KAT5（裂殖酵母 Mst1，人类 TIP60）是一种从酵母到人类都保守的 MYST 家族组蛋白乙酰转移酶，它协调 DNA DSB 处的各种 DNA 损伤反应活动，包括组蛋白重塑和 DNA 损伤检查点的激活。在裂殖酵母中，mst1+的突变导致对 DNA 损伤药物的敏感性。在这里，我们表明 Mst1 被招募到 DSB 处。mst1+的突变破坏了修复蛋白的募集并延迟了核酸酶的酶切。这些缺陷部分被 pku70 的缺失所挽救，pku70 先前已被证明拮抗同源重组 (HR) 的修复。mst1 的这些表型与 pht1-4KR 相似，pht1-4KR 是一种组蛋白变体 H2A.Z 的非乙酰化形式，它被认为会影响核酸酶的酶切。我们的数据表明，Mst1 通过调节 DSB 处的核酸酶的酶切来指导 DSB 向 HR 途径修复。
