Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA

Abstract

Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, which is required for transcription recovery post UV. We demonstrate that HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3 histones. However, this local activity of HIRA is dispensable for transcription recovery. Instead, we reveal a genome-wide function of HIRA in transcription restart that is independent of new H3.3 and not restricted to UV-damaged loci. HIRA coordinates with ASF1B to control transcription restart by two independent pathways: by stabilizing the associated subunit UBN2 and by reducing the expression of the transcription repressor ATF3. Thus, HIRA primes UV-damaged chromatin for transcription restart at least in part by relieving transcription inhibition rather than by depositing new H3.3 as an activating bookmark.

HIRA loss transforms FH -deficient cells

“…Furthermore, while HIRA has been shown to interact with c-MYC on chromatin, our work reveals an essential regulatory function of Myc activity by Hira , which is independent of its role as an H3.3 chaperone ( 32 ). This confirms a noncanonical function of HIRA, independent of its chaperone role, as previously observed in another study ( 33 ). Further investigation is needed to fully assess whether this function occurs at the chromatin level or outside of the nucleus and whether it is dependent on the deposition of the noncanonical histone H3.3 by HIRA.…”

Histone Variants: Guardians of Genome Integrity

“…FACT stimulates transcription restart after UV damage through the recruitment of the transcription-coupled repair factor UV-stimulated scaffold protein A (UVSSA) [110], but the implication of new histone H2A deposition in this process is not established. Furthermore, recent evidence shows that new H3.3 deposition by HIRA in UV damaged chromatin is actually dispensable for transcription restart, highlighting a non-canonical function of the histone chaperone HIRA in this context [111]. Thus, despite their likely contribution to the re-organization of chromatin after repair, the functional importance of newly deposited histones in damaged chromatin still needs to be determined.…”