DAXX promotes centromeric stability independently of ATRX by preventing the accumulation of R-loop-induced DNA double-stranded breaks

Abstract Maintaining chromatin integrity at the repetitive non-coding DNA sequences underlying centromeres is crucial to prevent replicative stress, DNA breaks and genomic instability. The concerted action of transcriptional repressors, chromatin remodelling complexes and epigenetic factors controls...

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Published in:	Nucleic acids research 2024-02, Vol.52 (3), p.1136-1155
Main Authors:	Pinto, Lia M, Pailas, Alexandros, Bondarchenko, Max, Sharma, Abhishek Bharadwaj, Neumann, Katrin, Rizzo, Anthony J, Jeanty, Céline, Nicot, Nathalie, Racca, Carine, Graham, Mindy K, Naughton, Catherine, Liu, Yaqun, Chen, Chun-Long, Meakin, Paul J, Gilbert, Nick, Britton, Sébastien, Meeker, Alan K, Heaphy, Christopher M, Larminat, Florence, Van Dyck, Eric
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Centromere - metabolism Child Chromatin Co-Repressor Proteins - metabolism DNA DNA Breaks, Double-Stranded Histones - genetics Histones - metabolism Humans Molecular Chaperones - genetics Molecular Chaperones - metabolism Nuclear Proteins - metabolism R-Loop Structures Transcription Factors - metabolism X-linked Nuclear Protein - genetics X-linked Nuclear Protein - metabolism
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Summary:	Abstract Maintaining chromatin integrity at the repetitive non-coding DNA sequences underlying centromeres is crucial to prevent replicative stress, DNA breaks and genomic instability. The concerted action of transcriptional repressors, chromatin remodelling complexes and epigenetic factors controls transcription and chromatin structure in these regions. The histone chaperone complex ATRX/DAXX is involved in the establishment and maintenance of centromeric chromatin through the deposition of the histone variant H3.3. ATRX and DAXX have also evolved mutually-independent functions in transcription and chromatin dynamics. Here, using paediatric glioma and pancreatic neuroendocrine tumor cell lines, we identify a novel ATRX-independent function for DAXX in promoting genome stability by preventing transcription-associated R-loop accumulation and DNA double-strand break formation at centromeres. This function of DAXX required its interaction with histone H3.3 but was independent of H3.3 deposition and did not reflect a role in the repression of centromeric transcription. DAXX depletion mobilized BRCA1 at centromeres, in line with BRCA1 role in counteracting centromeric R-loop accumulation. Our results provide novel insights into the mechanisms protecting the human genome from chromosomal instability, as well as potential perspectives in the treatment of cancers with DAXX alterations. Graphical Abstract Graphical Abstract
ISSN:	0305-1048 1362-4962