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Induction of readthrough of stop codons by aminoglycosides increases DNA repair in xeroderma pigmentosum group C cells

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • C Kuschal
  • J J DiGiovanna
  • SG Khan
  • KH Kraemer


Xeroderma pigmentosum is a rare recessive disorder with sun sensitivity and a 10,000-fold increase in skin cancers due to a defective nucleotide excision repair (NER). Many XP patients have mutations in the XPC gene that result in premature stop codons. In-vitro studies demonstrated that aminoglycosides like Geneticin are able to "read through" premature stop codon mutations, leading to partial induction of missing proteins in e.g. Duchenne muscular dystrophy and ataxia-telangiectasia. We investigated the effects of Geneticin on DNA repair in four XP-C patient cell lines: XP62DC, XP59DC and XP198BE had identical mutations (ARG>X) located in different regions, XP21BE had an initiation codon mutation. All cells show markedly reduced XPC mRNA, no detectable XPC protein and no repair of 6-4 photoproducts (6-4PP) and cyclobutane pyrimidine dimers (CPD). Geneticin treatment resulted in increased XPC mRNA and XPC protein in XP59DC and XP62DC but not in XP198BE or XP21BE cells. Only in XP59DC and XP62DC cells, XPC protein was visualized by immunofluorescence at sites of UV damage followed by recruitment of XPB and XPD DNA repair proteins with consequent repair of 6-4PP and CPD. Our findings provide evidence that Geneticin can partially induce XPC protein expression in some XPC-deficient cells with ARG>X mutations.

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