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Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2

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 C. West
doi: https://doi.org/10.1101/2021.05.07.443085
Radhakrishnan Kanagaraj
1DNA Recombination and Repair Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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  • For correspondence: stephen.west@crick.ac.uk
Richard Mitter
2Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Theodoros Kantidakis
3Aston Medical School, Aston University, Birmingham B4 7ET, UK
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Matthew M. Edwards
4Department of Molecular Biology and Genetics, Cornell University, Ithaca NY14853, USA
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Anaid Benitez
1DNA Recombination and Repair Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Probir Chakravarty
2Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Beiyuan Fu
5Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Olivier Becherel
6The University of Queensland Centre for Clinical Research, Herston, Queensland 4029, Australia
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Fengtang Yang
5Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Martin F. Lavin
6The University of Queensland Centre for Clinical Research, Herston, Queensland 4029, Australia
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Amnon Koren
4Department of Molecular Biology and Genetics, Cornell University, Ithaca NY14853, USA
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Aengus Stewart
2Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Stephen C. West
1DNA Recombination and Repair Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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  • For correspondence: stephen.west@crick.ac.uk
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ABSTRACT

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 Statement

The authors have declared no competing interest.

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Posted May 08, 2021.
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Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2
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 C. West
bioRxiv 2021.05.07.443085; doi: https://doi.org/10.1101/2021.05.07.443085
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Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2
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 C. West
bioRxiv 2021.05.07.443085; doi: https://doi.org/10.1101/2021.05.07.443085

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