2. Academic Validation
  3. DAXX promotes centromeric stability independently of ATRX by preventing the accumulation of R-loop-induced DNA double-stranded breaks

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

  • Nucleic Acids Res. 2023 Dec 1:gkad1141. doi: 10.1093/nar/gkad1141.
Lia M Pinto 1 2 3,  Alexandros Pailas 1 2,  Max Bondarchenko 1 2,  Abhishek Bharadwaj Sharma 1,  Katrin Neumann 1,  Anthony J Rizzo 4,  Céline Jeanty 1,  Nathalie Nicot 5,  Carine Racca 6,  Mindy K Graham 4,  Catherine Naughton 7,  Yaqun Liu 8,  Chun-Long Chen 8,  Paul J Meakin 3,  Nick Gilbert 7,  Sébastien Britton 6,  Alan K Meeker 4,  Christopher M Heaphy 9,  Florence Larminat 6,  Eric Van Dyck 1
Affiliations

Affiliations

  • 1 DNA Repair and Chemoresistance Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), L-1210 Luxembourg, Luxembourg.
  • 2 Faculty of Science, Technology and Communication, University of Luxembourg, L-4365 Esch-sur-Alzette, Luxembourg.
  • 3 Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
  • 4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 5 Translational Medicine Operations Hub, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
  • 6 Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), 31077 Toulouse Cedex 4, France.
  • 7 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh EH4 1QY, UK.
  • 8 Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université, 75248 Paris Cedex 05, France.
  • 9 Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
PMID: 38038252 DOI: 10.1093/nar/gkad1141
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.

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