The Histone Chaperone FACT Coordinates H2A.X-Dependent Signaling and Repair of DNA Damage

• Published in: Molecular cell Vol. 72; no. 5; pp. 888 - 901.e7
• Main Authors: Piquet, Sandra, Le Parc, Florent, Bai, Siau-Kun, Chevallier, Odile, Adam, Salomé, Polo, Sophie E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.12.2018; Cell Press
• Subjects: Alpha-Amanitin - pharmacology; Animals; ANP32E; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Line, Tumor; chromatin; Chromatin Assembly and Disassembly - drug effects; DNA - genetics; DNA - metabolism; DNA Damage; DNA damage signaling; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; FACT; Gene Expression Regulation; H2A.X; H2A.Z; High Mobility Group Proteins - genetics; High Mobility Group Proteins - metabolism; histone chaperones; histone variants; Histones - genetics; Histones - metabolism; Humans; Life Sciences; Mice; Morpholines - pharmacology; NIH 3T3 Cells; Nucleosomes - chemistry; Nucleosomes - drug effects; Nucleosomes - metabolism; Poisons - pharmacology; Pyrimidines - pharmacology; Pyrones - pharmacology; Signal Transduction; Transcriptional Elongation Factors - genetics; Transcriptional Elongation Factors - metabolism; UV damage; histone chaperones; histone variants; ANP32E; DNA damage signaling; chromatin; FACT; DNA repair; H2A.Z; UV damage; H2A.X
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.09.010

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. [Display omitted] •H2A.X is deposited de novo at sites of DNA damage repair, whereas H2A.Z is evicted•FACT promotes new H2A.X deposition coupled to repair synthesis•FACT stimulates H2A.X-dependent signaling of DNA damage•H2A.X is not only a starting point of damage signaling but also an output of repair Histone variants convey epigenetic information and define functional chromatin states. Piquet et al. describe a reshaping of histone variant patterns at sites of UVC damage repair with H2A.Z removal followed by de novo deposition of H2A.X. The H2A.X deposition machinery provides a means for fine-tuning DNA damage signaling.