• Home
  • Search Results
  • Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency.

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

Molecular cell (2021-02-12)
Ji-Hoon Lee, Seung W Ryu, Nicolette A Ender, Tanya T Paull
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Retinoic acid, ≥98% (HPLC), powder
Sigma-Aldrich
Sodium (meta)arsenite, ≥90%
Sigma-Aldrich
Anti-TMEM119 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
p-Xylene-bis(N-pyridinium bromide), ≥95% (TLC)
Sigma-Aldrich
Adipic acid dihydrazide–Agarose, saline suspension
Sigma-Aldrich
MISSION® esiRNA, targeting human ATM