Piquet Sandra, Le Parc Florent, Bai Siau-Kun, Chevallier Odile, Adam Salomé, Polo Sophie E
Epigenome Integrity Group, Epigenetics & Cell Fate Centre, UMR7216 CNRS, Paris Diderot University, Sorbonne Paris Cité, 75013 Paris, France.
Epigenome Integrity Group, Epigenetics & Cell Fate Centre, UMR7216 CNRS, Paris Diderot University, Sorbonne Paris Cité, 75013 Paris, France.
Mol Cell. 2018 Dec 6;72(5):888-901.e7. doi: 10.1016/j.molcel.2018.09.010. Epub 2018 Oct 18.
Safeguarding cell function and identity following a genotoxic stress challenge entails a tight coordination of DNA damage signaling and repair with chromatin maintenance. How this coordination is achieved and with what impact on chromatin integrity remains elusive. Here, we address these questions by investigating the mechanisms governing the distribution in mammalian chromatin of the histone variant H2A.X, a central player in damage signaling. We reveal that H2A.X is deposited de novo at sites of DNA damage in a repair-coupled manner, whereas the H2A.Z variant is evicted, thus reshaping the chromatin landscape at repair sites. Our mechanistic studies further identify the histone chaperone FACT (facilitates chromatin transcription) as responsible for the deposition of newly synthesized H2A.X. Functionally, we demonstrate that FACT potentiates H2A.X-dependent signaling of DNA damage. We propose that new H2A.X deposition in chromatin reflects DNA damage experience and may help tailor DNA damage signaling to repair progression.
在基因毒性应激挑战后保护细胞功能和特性需要DNA损伤信号传导与修复和染色质维持的紧密协调。这种协调是如何实现的以及对染色质完整性有何影响仍不清楚。在这里，我们通过研究调控组蛋白变体H2A.X（损伤信号传导中的核心参与者）在哺乳动物染色质中分布的机制来解决这些问题。我们发现H2A.X以与修复偶联的方式在DNA损伤位点从头沉积，而H2A.Z变体则被驱逐，从而重塑修复位点的染色质格局。我们的机制研究进一步确定组蛋白伴侣FACT（促进染色质转录）负责新合成的H2A.X的沉积。在功能上，我们证明FACT增强了H2A.X依赖的DNA损伤信号传导。我们提出染色质中新的H2A.X沉积反映了DNA损伤经历，并可能有助于根据修复进程调整DNA损伤信号传导。
