Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2
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Radhakrishnan Kanagaraj Richard Mitter Theodoros Kantidakis Matthew M Edwards Anaid Benitez Probir Chakravarty Beiyuan Fu Olivier Becherel Fengtang Yang Martin F Lavin Amnon Koren Aengus Stewart Stephen WestAbstract
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 genome-wide 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 mutation-associated chromosome fragility and AOA2.
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Volume 119
Issue number 4
Pages e2114314119
Available online
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Publisher website (DOI) 10.1073/pnas.2114314119
Europe PubMed Central 35042798
Pubmed 35042798
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