Journal Article

C9orf72 expansion disrupts ATM-mediated chromosomal break repair

Liao, Chunyan, Lewis, Katherine, Iannitti, Tommaso, Azzouz, Mimoun, Herranz-Martin, Saul, Hassan, Mohamed K, Shaw, Pamela J, Karyka, Evangelia, Chiang, Shih-Chieh, Coldicott, Ian, Tsagakis, Ioannis, Mulcahy, Padraig J, Jurga, Mateusz, El-Khamisy, Sherif F, De Vos, Kurt J, Hautbergue, Guillaume M, Higginbottom, Adrian, Chandran, Jayanth, Walker, Callum, Elsayed, Waheba, Lukashchuk, Vera, Ray, Swagat

2017

Overview

An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death. Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA–RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9 orf 72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/106 / 14/19 / 14/32 / 14/63 / 42 / 42/34 / 42/41 / 42/44 / 631/378/1689/1285 / 631/378/1934 / 631/80/304 / 64 / 692/699/375/365 / Accumulation / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animal Genetics and Genomics / Animals / Ataxia Telangiectasia Mutated Proteins - genetics / Ataxia Telangiectasia Mutated Proteins - metabolism / Behavioral Sciences / Bioaccumulation / Biological Techniques / Biomedicine / C9orf72 Protein / Cells, Cultured / Central nervous system / Chromosome abnormalities / Chromosome Breakage / Damage accumulation / Dementia disorders / Deoxyribonucleic acid / Development and progression / DNA / DNA damage / DNA repair / DNA Repair - physiology / DNA Repeat Expansion - physiology / Frontotemporal dementia / Gene expression / Gene mutation / Genetic aspects / Genomic instability / Health aspects / HEK293 Cells / Humans / Hybrids / Mice / Mice, Inbred C57BL / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurosciences / Open reading frames / Proteins - genetics / Proteins - metabolism / R-loops / Random Allocation / Rats / Repair / Ribonucleic acid / RNA / Spinal cord / Spinal Cord - metabolism / Spinal Cord - pathology / Stability / Tissues / Ubiquitin / Viruses