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Title: C9orf72 expansions disrupt ATM-mediated DNA repair
Author: Walker, Callum
ISNI:       0000 0004 7228 5076
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Hexanucleotide repeat expansions, contained within the C9orf72 gene, represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), though the mechanisms by which such expansions cause neurodegeneration are poorly understood. Here, we report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks (DSBs) in human cells, rodent neurons, and C9orf72 ALS patient tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM- and 53BP1-mediated DNA repair signalling, and the accumulation of protein-linked DNA breaks. We reveal that defective DNA repair is a consequence of p62 accumulation, which impairs H2A ubiquitylation, and perturbs ATM signalling. These findings identify R-loops, double strand breaks, and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven, at least partly, by genomic instability.
Supervisor: Sherif, El-Khamisy ; Mimoun, Azzouz Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available