Herbette M, Mercier M G, Michal F, Cluet D, Burny C, Yvert G, Robert V J, Palladino F
Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, Université Lyon 1, 46 allée d'Italie, 69007 Lyon, France.
Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, Université Lyon 1, 46 allée d'Italie, 69007 Lyon, France.
DNA Repair (Amst). 2017 Sep;57:139-150. doi: 10.1016/j.dnarep.2017.07.007. Epub 2017 Jul 29.
Maintaining the integrity of genetic information across generations is essential for both cell survival and reproduction, and requires the timely repair of DNA damage. Histone-modifying enzymes play a central role in the DNA repair process through the deposition and removal of post-translational modifications on the histone tails. Specific histone modification act in the DNA repair process through the recruitment of proteins and complexes with specific enzymatic activities, or by altering the chromatin state at the site of DNA lesions. The conserved SET1/MLL family of histone methyltransferases (HMT) catalyzes methylation of histone H3 on Lysine 4 (H3K4), a histone modification universally associated with actively transcribed genes. Studies have focused on the role of SET1/MLL proteins in epigenetic regulation of gene expression. Much less is known on their role in the DNA repair process in a developmental context. Here we show that SET-2, the Caenorhabditis elegans orthologue of SET1, is required to preserve germline genome integrity over subsequent generations. Animals lacking the SET-2 catalytic subunit show a transgenerational increase in sensitivity to DNA damage-inducing agents that is accompanied by a defect in double-strand break (DSB) repair and chromosome fragmentation. These defects are not due to a failure to activate the DNA damage response (DDR) that allows detection, signaling and repair of DNA lesions, because cell cycle arrest and apoptosis, key components of this pathway, are efficiently induced in set-2 mutant animal. Rather, our results suggest that SET-2 plays a role in the transgenerational maintenance of genome stability by acting in DNA repair downstream of DDR signaling.
跨代维持遗传信息的完整性对于细胞存活和繁殖至关重要，并且需要及时修复DNA损伤。组蛋白修饰酶通过在组蛋白尾部进行翻译后修饰的沉积和去除，在DNA修复过程中发挥核心作用。特定的组蛋白修饰通过招募具有特定酶活性的蛋白质和复合物，或通过改变DNA损伤位点的染色质状态，在DNA修复过程中发挥作用。保守的SET1/MLL组蛋白甲基转移酶（HMT）家族催化组蛋白H3赖氨酸4（H3K4）位点的甲基化，这种组蛋白修饰普遍与活跃转录的基因相关。研究主要集中在SET1/MLL蛋白在基因表达表观遗传调控中的作用。而对于它们在发育背景下的DNA修复过程中的作用了解较少。在此，我们表明SET-2，即秀丽隐杆线虫中SET1的直系同源物，是维持后代生殖系基因组完整性所必需的。缺乏SET-2催化亚基的动物对DNA损伤诱导剂的敏感性呈现跨代增加，同时伴有双链断裂（DSB）修复缺陷和染色体片段化。这些缺陷并非由于未能激活允许检测、信号传导和修复DNA损伤的DNA损伤应答（DDR），因为该途径的关键组成部分细胞周期停滞和凋亡在set-2突变动物中能够有效诱导。相反，我们的结果表明SET-2通过在DDR信号传导下游的DNA修复中发挥作用，在基因组稳定性的跨代维持中发挥作用。
