In eukaryotic cells, the homology-directed repair (HDR) and non-homologous end joining (NHEJ) pathways are required for the repair of DNA double strand breaks (DSB). The high-fidelity HDR pathway is particularly important for maintenance of genomic stability. In mammals, histone post-translational modifications and histone variant exchange into nucleosomes at sites of DSB generate an open chromatin state necessary for repair to take place. However, the specific contributions of histone modifications to histone variant exchange at DSB sites and the influence of these changes on the DNA repair process and genome stability are incompletely understood. Here we show that Dot1L-catalyzed methylation of H3 histone on lysine 79 (H3K79) is required for efficient HDR of DSB. In cells with DNA DSB either lacking Dot1L or expressing a methylation-dead Dot1L, there is altered kinetics of DNA repair factor recruitment, markedly decreased H2A.Z incorporation at DSB sites, and a specific and profound reduction in HDR, which results in significant genomic instability. These findings demonstrate a new role for Dot1L, identifying it as a critical regulator of the DNA repair process and a steward of genomic integrity.

中文翻译：

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Dot1L依赖的H3K79甲基化可促进DNA双链断裂处的组蛋白变体H2A.Z交换，并且是高保真，同源性指导的DNA修复所必需的

在真核细胞中，DNA双链断裂（DSB）的修复需要同源性定向修复（HDR）和非同源末端连接（NHEJ）途径。高保真HDR途径对于维持基因组稳定性特别重要。在哺乳动物中，组蛋白的翻译后修饰和组蛋白变体在DSB的位点交换成核小体，会产生开放的染色质状态，这是修复发生所必需的。但是，尚不完全了解组蛋白修饰对DSB位点组蛋白变体交换的特定贡献以及这些变化对DNA修复过程和基因组稳定性的影响。在这里，我们显示了DSB的有效HDR需要赖氨酸79（H3K79）上Dot1L催化的H3组蛋白的甲基化。在具有DNA DSB的细胞中缺少Dot1L或表达甲基化死的Dot1L，DNA修复因子募集的动力学发生了变化，DSB位点的H2A.Z掺入显着降低，HDR发生了显着的大幅下降，这导致了显着的基因组不稳定。这些发现证明了Dot1L的新作用，将其确定为DNA修复过程的关键调节剂和基因组完整性的管理者。