Nucleotide excision repair and the 26S proteasome function together to promote trinucleotide repeat expansions

DNA Repair (Amst). 2014 Jan;13:42-9. doi: 10.1016/j.dnarep.2013.11.004. Epub 2013 Dec 17.


Trinucleotide repeat (TNR) expansion underpins a number of inheritable neurological human disorders. Multiple mechanisms are thought to contribute to the expansion process. The incorrect processing of the repeat tract by DNA repair proteins can drive this mutation process forward, as expansions are suppressed following ablation of certain repair factors in mouse models and cell models of disease. Nucleotide excision repair (NER) is one repair pathway implicated in TNR instability, although most previous work focussed on TNR contractions, not expansions. Here we investigated the role of NER in modulating expansions of threshold-length (CTG·CAG) repeats in yeast. We show that both the global genome and transcription-coupled repair subpathways promote expansions of threshold-length TNRs. Furthermore, NER works with the 26S proteasome to drive expansions, based on analysis of double mutants defective in both pathways, and of Rad23, a protein involved in both NER and the shuttling of ubiquitinated proteins to the proteasome. This work provides the first evidence that both subpathways of NER can promote threshold-length TNR expansions and that NER interacts with the proteasome to drive expansions.

Keywords: BER; GG-NER; HD; Huntington's disease; NER; R4B; Rad4 binding domain; SC-Trp; SCA1; SEM; TC-NER; TNR; UBA; UBL; YPD; base excision repair; global genome nucleotide excision repair; nucleotide excision repair; spinocerebellar ataxia type 1; standard error of the mean; synthetic complete medium lacking tryptophan; transcription-coupled nucleotide excision repair; trinucleotide repeat; ubiquitin-associated domain; ubiquitin-like domain; w.t.; wild type; yeast extract–peptone–dextrose medium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • DNA Repair*
  • Genome, Fungal
  • Genomic Instability
  • Humans
  • Mice
  • Mutation
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / physiology*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Trinucleotide Repeat Expansion*
  • Ubiquitination


  • Saccharomyces cerevisiae Proteins
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • DNA Repair Enzymes