Deciphering the role of the ERCC2 gene polymorphism on anticancer drug sensitivity

Carcinogenesis
François MoisanValérie Le Morvan

Abstract

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 Gln(751) 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 G(2)/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,...Continue Reading

References

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Citations

Jun 28, 2014·Asian Pacific Journal of Cancer Prevention : APJCP·Li-Ming HuangXue-De Lin
Aug 12, 2014·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Jacques RobertUNKNOWN PAMM Group of EORTC
Apr 5, 2018·Frontiers in Molecular Biosciences·Aga Syed Sameer, Saniya Nissar

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