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Status |
Public on Apr 29, 2021 |
Title |
Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2. |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
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 RNA polymerase II pausing events (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. Aberrant R-loops were resolved by transcription-coupled repair (TCR), in reactions dependent upon the Cockayne Syndrome protein CSB. We found that CSB was required for the recruitment of the TCR endonucleases XPG and XPF, and recombination factors to target and resolve transcription bubbles containing R-loops and promote genomic instability. These results show that cells derived from individuals with Ataxia with Oculomotor Apraxia 2 exhibit transcription stress giving rise to genome-wide chromosomal fragility, termed transcription stress-induced fragile sites (TSFS), in transcribed regions of the mammalian genome.
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Overall design |
Examination of gene expression profiles in AOA2 and control (CTRL) lymphoblastoid cell lines by Affymetrix Human Gene 1.0 ST microarrays.
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Contributor(s) |
Kanagaraj R, Chakravarty P, West SC |
Citation(s) |
- Kanagaraj R, Mitter R, Kantidakis T, Edwards MM et al. Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2. Proc Natl Acad Sci U S A 2022 Jan 25;119(4). PMID: 35042798
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Submission date |
Jan 14, 2020 |
Last update date |
Feb 08, 2022 |
Contact name |
Steve West |
E-mail(s) |
stephen.west@crick.ac.uk
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Organization name |
The Francis Crick Institute
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Street address |
1 Midland Road
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City |
London |
ZIP/Postal code |
NW1 1AT |
Country |
United Kingdom |
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Platforms (1) |
GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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Samples (24)
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This SubSeries is part of SuperSeries: |
GSE143574 |
Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2 |
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Relations |
BioProject |
PRJNA601222 |