Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function.
Nucleic Acids Res
10042 - 10055
Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Cell Survival, Cells, Cultured, DNA Repair, Fibroblasts, Humans, Molecular Chaperones, Oxidation-Reduction, Oxidative Stress, Proteasome Endopeptidase Complex, Protein Biosynthesis, Proteostasis Deficiencies, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Recombinant Proteins, Unfolded Protein Response