Transcription Recovery after DNA Damage Requires Chromatin Priming by the H3.3 Histone Chaperone HIRA

• Published in: Cell Vol. 155; no. 1; pp. 94 - 106
• Main Authors: Adam, Salomé, Polo, Sophie E., Almouzni, Geneviève
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2013; Elsevier
• Subjects: Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromatin; DNA damage; DNA Damage - radiation effects; DNA Repair; genotoxicity; HeLa Cells; Histone Chaperones - metabolism; histones; Histones - metabolism; Humans; irradiation; Life Sciences; transcription (genetics); Transcription Factors - metabolism; Transcription, Genetic; Ubiquitination; Ultraviolet Rays
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.08.029

Understanding how to recover fully functional and transcriptionally active chromatin when its integrity has been challenged by genotoxic stress is a critical issue. Here, by investigating how chromatin dynamics regulate transcriptional activity in response to DNA damage in human cells, we identify a pathway involving the histone chaperone histone regulator A (HIRA) to promote transcription restart after UVC damage. Our mechanistic studies reveal that HIRA accumulates at sites of UVC irradiation upon detection of DNA damage prior to repair and deposits newly synthesized H3.3 histones. This local action of HIRA depends on ubiquitylation events associated with damage recognition. Furthermore, we demonstrate that the early and transient function of HIRA in response to DNA damage primes chromatin for later reactivation of transcription. We propose that HIRA-dependent histone deposition serves as a chromatin bookmarking system to facilitate transcription recovery after genotoxic stress. [Display omitted] •Transcription recovery after UVC damage involves an H3.3 histone chaperone•The histone chaperone HIRA deposits new H3.3 histones in UVC-damaged chromatin•Ubiquitylation associated with damage detection targets HIRA to damaged regions•HIRA primes damaged chromatin for transcription restart after repair Transient targeting of HIRA to damaged chromatin regions deposits newly synthesized H3.3 histones, “bookmarking” the chromatin substrate for reactivation of transcription once repair is complete.