A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy

Somers, J. et al. (2015) A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy. Genes and Development, 29(18), pp. 1891-1896. (doi: 10.1101/gad.261867.115) (PMID:26338418) (PMCID:PMC4579346)

Abstract

We show that a common polymorphic variant in the ERCC5 5′ untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5′ noncoding mRNA element influences individuals’ responses to platinum-based chemotherapy.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bushell, Professor Martin
• Authors: Somers, J., Wilson, L. A., Kilday, J.-P., Horvilleur, E., Cannell, I. G., Pöyry, T. A.A., Cobbold, L. C., Kondrashov, A., Knight, J. R.P., Puget, S., Grill, J., Grundy, R. G., Bushell, M., and Willis, A. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Genes and Development
• Publisher: Cold Spring Harbor Laboratory
• ISSN: 0890-9369
• ISSN (Online): 1549-5477
• Published Online: 03 September 2015
• Copyright Holders: Copyright © 2015 Somers et al.
• First Published: First published in Genes and Development 29(18): 1891-1896
• Publisher Policy: Reproduced under a Creative Commons License