Abstract：
Histone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.
摘要：
组蛋白H3Lys36（H3K36）甲基化及其相关修饰因子对于DNA双链断裂（DSB）修复至关重要，但不同的H3K36甲基化是否以及如何影响修复途径的机制尚不清楚.这里,我们揭示了H3K36二甲基化（H3K36me2）和H3K36三甲基化（H3K36me3）在DSB修复中通过非同源末端连接（NHEJ）或同源重组（HR）的不同作用。缺乏H3K36me2或H3K36me3的酵母细胞表现出降低的NHEJ或HR效率。yKu70和Rfa1结合H3K36me2-或H3K36me3修饰的肽和染色质，分别。破坏这些相互作用会损害yKu70和Rfa1对受损的H3K36me2-或富含H3K36me3的基因座的募集，增加DNA损伤敏感性和降低修复效率。相反，在DSB胁迫下，富含H3K36me2的基因间区域和富含H3K36me3的基因体独立招募yKu70或Rfa1。重要的是,人类KU70和RPA1，即yKu70和Rfa1的同源物，以保守的方式与H3K36me2和H3K36me3完全相关。这些发现为H3K36me2和H3K36me3如何调节不同的DSB修复途径提供了有价值的见解。强调H3K36甲基化是选择DSB修复途径的关键因素。
