Jha Deepak Kumar, Strahl Brian D
Department of Biochemistry and Biophysics, School of Medicine, UNC-Chapel Hill, North Carolina, USA.
1] Department of Biochemistry and Biophysics, School of Medicine, UNC-Chapel Hill, North Carolina, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine, UNC-Chapel Hill, North Carolina 27599, USA.
Nat Commun. 2014 Jun 9;5:3965. doi: 10.1038/ncomms4965.
Histone modifications are major determinants of DNA double-strand break (DSB) response and repair. Here we elucidate a DSB repair function for transcription-coupled Set2 methylation at H3 lysine 36 (H3K36me). Cells devoid of Set2/H3K36me are hypersensitive to DNA-damaging agents and site-specific DSBs, fail to properly activate the DNA-damage checkpoint, and show genetic interactions with DSB-sensing and repair machinery. Set2/H3K36me3 is enriched at DSBs, and loss of Set2 results in altered chromatin architecture and inappropriate resection during G1 near break sites. Surprisingly, Set2 and RNA polymerase II are programmed for destruction after DSBs in a temporal manner--resulting in H3K36me3 to H3K36me2 transition that may be linked to DSB repair. Finally, we show a requirement of Set2 in DSB repair in transcription units--thus underscoring the importance of transcription-dependent H3K36me in DSB repair.
组蛋白修饰是DNA双链断裂（DSB）反应和修复的主要决定因素。在此，我们阐明了转录偶联的组蛋白H3赖氨酸36位点甲基化（H3K36me）在DSB修复中的功能。缺乏Set2/H3K36me的细胞对DNA损伤剂和位点特异性DSB高度敏感，无法正确激活DNA损伤检查点，并与DSB传感和修复机制表现出遗传相互作用。Set2/H3K36me3在DSB处富集，Set2的缺失导致染色质结构改变以及G1期靠近断裂位点处的不适当切除。令人惊讶的是，Set2和RNA聚合酶II在DSB后会按时间顺序被编程降解，导致H3K36me3向H3K36me2转变，这可能与DSB修复有关。最后，我们证明了转录单元中DSB修复需要Set2，从而强调了转录依赖性H3K36me在DSB修复中的重要性。
