J Somers, LA Wilson, J-P Kilday, E Horvilleur, IG Cannell, TAA Pöyry, LC Cobbold, A Kondrashov, JRP Knight, S Puget, J Grill, RG Grundy, M Bushell, AE Willis
Journal name: 
Genes Dev
Citation info: 
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.
E-pub date: 
31 Aug 2015
Users with this publication listed: 
Ian Cannell