Identification of a novel DNA oxidative damage repair pathway, requiring the ubiquitination of the histone variant macroH2A1.1

Khalid Ouararhni, Flore Mietton, Jamal S.M. Sabir, Abdulkhaleg Ibrahim, Annie Molla, Raed S. Albheyri, Ali T. Zari, Ahmed Bahieldin, Hervé Menoni, Christian Bronner, Stefan Dimitrov*, Ali Hamiche*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. The available data suggest that the histone variant mH2A participates in the regulation of transcription, maintenance of heterochromatin, NAD+ metabolism, and double-strand DNA repair. Results: Here, we describe a novel function of mH2A, namely its implication in DNA oxidative damage repair through PARP-1. The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin. Conclusions: Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation.

Original languageEnglish
Article number188
JournalBMC Biology
Volume22
Issue number1
DOIs
Publication statusPublished - Dec 2024
Externally publishedYes

Keywords

  • Chromatin
  • DNA repair
  • Histone variant
  • PARP-1
  • mH2A

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