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

Abstract

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 high levels of 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 (ATLD) mutants also show PARP-dependent aggregation identical to that of 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. These results provide a new hypothesis for loss of protein integrity and cerebellum function in A-T.