XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
Nature
; 541(7635): 87-91, 2017 01 05.
Article
in En
| MEDLINE
| ID: mdl-28002403
ABSTRACT
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cerebellar Ataxia
/
DNA-Binding Proteins
/
Poly (ADP-Ribose) Polymerase-1
/
Mutation
Type of study:
Risk_factors_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nature
Year:
2017
Document type:
Article
Affiliation country:
United kingdom