Walker, C., Herranz-Martin, S., Karyka, E. et al. (19 more authors) (2017) C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair. Nature Neuroscience, 20 (9). pp. 1225-1235. ISSN 1097-6256
Abstract
A hexanucleotide repeat expansion represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which the expansion cause neurodegeneration are poorly understood. We report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signalling and accumulation of protein-linked DNA breaks. We further reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus- mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration. These findings identify R-Loops, DSBs, and defective ATM-mediated repair as pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked neurodegeneration is driven, at least in part, by genomic instability.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 Nature Publishing Group. This is an author produced version of a paper subsequently published in Nature Neuroscience. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number EUROPEAN RESEARCH COUNCIL GTNCTV - 294745 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Jul 2017 14:24 |
Last Modified: | 02 Nov 2023 16:39 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/nn.4604 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:118606 |