Journal Article

Deciphering the role of the <i>ERCC2</i> gene polymorphism on anticancer drug sensitivity

François Moisan, Audrey Laroche-Clary, Céline Auzanneau, Nicolas Ricard, Philippe Pourquier, Jacques Robert and Valérie Le Morvan

in Carcinogenesis

Volume 33, issue 5, pages 962-968
Published in print May 2012 | ISSN: 0143-3334
Published online February 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs107
Deciphering the role of the ERCC2 gene polymorphism on anticancer drug sensitivity

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ERCC2 [Xeroderma pigmentosum (XP) group D] belongs to the nucleotide excision repair pathway. It is also part of the TFIIH transcription complex and is required for the association of the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex with TFIIH. Using the NCI-60 panel of human tumor cell lines, we had shown that the ERCC2 gene variant Gln751 was significantly associated to increased taxanes sensitivity and decreased ERCC2 gene expression. Since TFIIH is involved in both DNA repair and cell cycle progression, we hypothesized that quantitative or qualitative ERCC2 alterations might cause CAK liberation, allowing its activation of the G2/M transition. Enhancing mitosis entry would lead to hypersensitivity to spindle poisons, explaining the effect of ERCC2 polymorphisms on taxane sensitivity. Starting from ERCC2-deficient XP6BE, we generated several isogenic clones differing only by the Lys751Gln variation. Wild-type and variant ERCC2-expressing clones recovered ultraviolet radiation and cisplatin resistance but presented similar sensitivity to paclitaxel, demonstrating that the amino acid change was not involved in paclitaxel differential sensitivity in the NCI-60 panel. Using small interfering RNA approach, we knocked down ERCC2 expression and observed a block in the G2/M phase, with a consistent increase in paclitaxel sensitivity and no change in cisplatin sensitivity. We observed in addition an increase in CDK1 activity, as evaluated by histone H1 phosphorylation. We evaluated messenger RNA (mRNA) half-life in the isogenic lines and observed a more rapid degradation in cells bearing the variant construct. We concluded that the increased paclitaxel sensitivity of ERCC2 variant cell lines is a consequence of lower gene expression, likely due to decreased stability of the variant ERCC2 mRNA.

Journal Article.  5430 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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