Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases ataxia with oculomotor apraxia 2 (AOA2) and amyotrophic lateral sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. A genomewide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites was observed, resulting in changes to gene-expression profiles. Transcription stress near promoters correlated with high GCskew and the accumulation of R-loops at promoter-proximal regions, which localized with chromosomal regions where gains and losses were observed. In the absence of Senataxin, the Cockayne syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and RAD52 recombination protein to target and resolve transcription bubbles containing R-loops, leading to genomic instability. These results show that transcription stress is an important contributor to SETX mutationassociated chromosome fragility and AOA2.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 25 Jan 2022|
Bibliographical noteCopyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Services, Flow Cytometry and Advanced Sequencing facilities for cell culture, Imagestream, and sequencing support. This work was supported by the Francis Crick Institute (FC10212), the European Research Council (ERC-ADG-249145 and ERC-ADG-666400), and the Louis-Jeantet Foundation. The Francis Crick Institute receives core funding from Cancer Research UK, the Medical Research Council, and the Wellcome Trust. As this research was funded in part by the Wellcome Trust, for the purpose of Open Access the authors have applied a CC BY public copyright license. R.K. was the recipient of fellowships from the Swiss National Science Foundation (PBZHP3-138777 and PA00P3-142187).
- Ataxia with oculomotor apraxia
- DNA repair senataxin
- Transcription stress