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

Hum Mol Genet. 2011 Dec 15;20(24):4822-30. doi: 10.1093/hmg/ddr421. Epub 2011 Sep 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • 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*


  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Xeroderma Pigmentosum Group A Protein
  • Xpa protein, mouse