Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1.

Details

Serval ID
serval:BIB_A30AB82632B0
Type
Article: article from journal or magazin.
Collection
Publications
Title
Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1.
Journal
Human Molecular Genetics
Author(s)
Hubert L., Lin Y., Dion V., Wilson J.H.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Publication state
Published
Issued date
2011
Volume
20
Number
24
Pages
4822-4830
Language
english
Abstract
Expansion of trinucleotide repeats (TNRs) is responsible for a number of human neurodegenerative disorders. The molecular mechanisms that underlie TNR instability in humans are not clear. Based on results from model systems, several mechanisms for instability have been proposed, all of which focus on the ability of TNRs to form alternative structures during normal DNA transactions, including replication, DNA repair and transcription. These abnormal structures are thought to trigger changes in TNR length. We have previously shown that transcription-induced TNR instability in cultured human cells depends on several genes known to be involved in transcription-coupled nucleotide excision repair (NER). We hypothesized that NER normally functions to destabilize expanded TNRs. To test this hypothesis, we bred an Xpa null allele, which eliminates NER, into the TNR mouse model for spinocerebellar ataxia type 1 (SCA1), which carries an expanded CAG repeat tract at the endogenous mouse Sca1 locus. We find that Xpa deficiency does not substantially affect TNR instability in either the male or female germline; however, it dramatically reduces CAG repeat instability in neuronal tissues-striatum, hippocampus and cerebral cortex-but does not alter CAG instability in kidney or liver. The tissue-specific effect of Xpa deficiency represents a novel finding; it suggests that tissue-to-tissue variation in CAG repeat instability arises, in part, by different underlying mechanisms. These results validate our original findings in cultured human cells and suggest that transcription may induce NER-dependent TNR instability in neuronal tissues in humans.
Keywords
Animals, Disease Models, Animal, Female, Gene Expression Regulation, Genetic Loci/genetics, Genomic Instability/genetics, Germ Cells/metabolism, Humans, Kidney/metabolism, Male, Mice, Mice, Inbred C57BL, Neostriatum/metabolism, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neurons/metabolism, Neurons/pathology, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Organ Specificity, Spinocerebellar Ataxias/genetics, Spinocerebellar Ataxias/pathology, Trinucleotide Repeat Expansion/genetics, Xeroderma Pigmentosum Group A Protein/genetics, Xeroderma Pigmentosum Group A Protein/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
27/02/2014 9:51
Last modification date
20/08/2019 15:08
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