Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

• Published in: Molecular cell Vol. 81; no. 7; pp. 1515 - 1533.e5
• Main Authors: Lee, Ji-Hoon, Ryu, Seung W., Ender, Nicolette A., Paull, Tanya T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Adult; ataxia; Ataxia Telangiectasia Mutated Proteins - deficiency; ATM; Cell Line, Tumor; DNA Breaks, Single-Stranded; DNA damage; DNA repair; Female; Humans; Male; MRE11; MRE11 Homologue Protein - deficiency; Neocortex - metabolism; Neocortex - pathology; PARP; Poly ADP Ribosylation; poly-ADP-ribose; protein aggregation; Proteostasis; R-loops; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Spinocerebellar Ataxias - pathology; MRE11; ataxia; poly-ADP-ribose; protein aggregation; DNA damage; ATM; PARP; R-loops; DNA repair
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.019

Loss of the ataxia-telangiectasia mutated (ATM) kinase causes cerebellum-specific neurodegeneration in humans. We previously demonstrated that deficiency in ATM activation via oxidative stress generates insoluble protein aggregates in human cells, reminiscent of protein dysfunction in common neurodegenerative disorders. Here, we show that this process is driven by poly-ADP-ribose polymerases (PARPs) and that the insoluble protein species arise from intrinsically disordered proteins associating with PAR-associated genomic sites in ATM-deficient cells. The lesions implicated in this process are single-strand DNA breaks dependent on reactive oxygen species, transcription, and R-loops. Human cells expressing Mre11 A-T-like disorder mutants also show PARP-dependent aggregation identical to ATM deficiency. Lastly, analysis of A-T patient cerebellum samples shows widespread protein aggregation as well as loss of proteins known to be critical in human spinocerebellar ataxias that is not observed in neocortex tissues. These results provide a hypothesis accounting for loss of protein integrity and cerebellum function in A-T. [Display omitted] •PARP activity drives protein aggregation in ATM-deficient human cells•Reactive oxygen species and R-loops contribute to the aggregation propensity•Loss of Mre11 is similar to ATM deficiency•Protein aggregates are abundant in A-T patient cerebellum tissue but not in cortex Lee et al. show that loss of protein homeostasis in ATM-deficient human cells is driven by PARP activity and transcription-associated DNA damage. Poly-ADP-ribose and protein aggregates are higher in A-T patient cerebellum tissue samples, consistent with a pathological role for these species in A-T patient neurodegeneration.