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University of Texas at Austin

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Mol. Cell, Volume 81, Issue 7, 1 April 2021, Pages 1515-1533.e5 | https://doi.org/10.1016/j.molcel.2021.01.019 Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

Ji-Hoon Lee¹Seung W. Ryu¹Nicolette A. Ender¹ Tanya T.Paull^1,2

¹The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX 78712, USA
²Lead contact

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 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.

논문정보

형식Research article
게재일2021년 04월 (BRIC 등록일 2021-09-23)
연구진국외 연구진
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