H2A.Z is required to initiate DNA repair to prevent premature aging

Histone variants are key epigenetic players, but their functional and physiological roles remain poorly understood. Here, we show that depletion of the histone variant H2A.Z in mouse skeletal muscle causes oxidative stress, oxidation of proteins, accumulation of DNA damages, and both neuromuscular junction and mitochondria lesions that consequently lead to premature muscle aging and reduced life span. Investigation of the molecular mechanisms involved shows that H2A.Z is required to initiate DNA double strand break repair by recruiting Ku80 at DNA lesions. This is achieved via specific interactions of Ku80 vWA domain with H2A.Z. Taken as a whole, our data reveal that H2A.Z containing nucleosomes act as a molecular platform to bring together the proteins required to initiate and process DNA double strand break repair. To adress the effect of H2A.Z on transcription, we have used skeletal muscles isolated from WT and H2A.Z null 12 months-old animals组蛋白变体（histone variant）是关键的表观遗传调控因子，但其功能与生理作用仍有待深入阐释。本研究显示，小鼠骨骼肌中组蛋白变体H2A.Z的缺失会引发氧化应激、蛋白质氧化损伤、DNA损伤蓄积，同时造成神经肌肉接头与线粒体病变，最终导致肌肉过早衰老及寿命缩短。对相关分子机制的研究表明，H2A.Z可通过在DNA损伤位点招募Ku80，启动DNA双链断裂修复过程。该功能通过Ku80的vWA结构域与H2A.Z的特异性相互作用实现。综上，本研究数据揭示，携带H2A.Z的核小体可作为分子平台，聚集启动并执行DNA双链断裂修复所需的各类蛋白质。为探究H2A.Z对转录的调控作用，我们使用了从12月龄野生型（Wild Type, WT）与H2A.Z基因敲除（H2A.Z null）小鼠中分离得到的骨骼肌组织。