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

Ji-Hoon Lee, Seung W Ryu, Nicolette A Ender, Tanya T Paull

Molecular cell 2021 Apr 01

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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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Ji-Hoon Lee, Seung W Ryu, Nicolette A Ender, Tanya T Paull. Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency. Molecular cell. 2021 Apr 01;81(7):1515-1533.e5