RT Journal Article SR Electronic T1 Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.07.443085 DO 10.1101/2021.05.07.443085 A1 Radhakrishnan Kanagaraj A1 Richard Mitter A1 Theodoros Kantidakis A1 Matthew M. Edwards A1 Anaid Benitez A1 Probir Chakravarty A1 Beiyuan Fu A1 Olivier Becherel A1 Fengtang Yang A1 Martin F. Lavin A1 Amnon Koren A1 Aengus Stewart A1 Stephen C. West YR 2021 UL http://biorxiv.org/content/early/2021/05/08/2021.05.07.443085.abstract AB 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. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased transcription stress near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. In the absence of Senataxin, we found that Cockayne Syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and recombination protein RAD52 to target and resolve transcription bubbles containing R-loops, leading to error prone repair and genomic instability. These results show that transcription stress is an important contributor to SETX mutation-associated chromosome fragility and AOA2.Competing Interest StatementThe authors have declared no competing interest.