Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency.
Mol Cell
; 81(7): 1515-1533.e5, 2021 04 01.
Article
en En
| MEDLINE
| ID: mdl-33571423
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neocórtex
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Ataxias Espinocerebelosas
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Roturas del ADN de Cadena Simple
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Proteínas de la Ataxia Telangiectasia Mutada
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Proteína Homóloga de MRE11
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Poli ADP Ribosilación
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Proteostasis
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos