Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency.
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.
['Lee|Ji-Hoon|JH|', 'Ryu|Seung W|SW|', 'Ender|Nicolette A|NA|', 'Paull|Tanya T|TT|']
D000328:Adult D064007:Ataxia Telangiectasia Mutated Proteins D045744:Cell Line, Tumor D053904:DNA Breaks, Single-Stranded D005260:Female D006801:Humans D000076228:MRE11 Homologue Protein D008297:Male D019579:Neocortex D000074747:Poly ADP Ribosylation D000074702:Proteostasis D020754:Spinocerebellar Ataxias
ATM MRE11 protein aggregation poly-ADP-ribose PARP R-loops ataxia DNA damage DNA repair