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

Genes & Development
Joanna SomersAnne E Willis

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.

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Citations

Apr 27, 2016·Nature Reviews. Cancer·Morgan L Truitt, Davide Ruggero
Jun 18, 2016·Science·Alan G HinnebuschNahum Sonenberg
Jul 11, 2018·Wiley Interdisciplinary Reviews. RNA·Graham D Pavitt
Jul 16, 2017·Biochemical Society Transactions·Robert HarveyAnne E Willis
Jan 24, 2017·Frontiers in Pharmacology·Gabriella LupoCarmelina D Anfuso
Oct 7, 2018·Human Genetics·Julie PlaisanciéM Corton
Nov 17, 2016·Nature Reviews. Molecular Cell Biology·Kassie S Manning, Thomas A Cooper
Nov 15, 2018·Frontiers in Genetics·Francis Robert, Jerry Pelletier
Apr 9, 2020·Frontiers in Pharmacology·Jiabei ZhouLushan Yu
Sep 26, 2020·Annual Review of Pharmacology and Toxicology·Abdelbaset A ElzagallaaiMichael J Rieder
Jan 15, 2021·Journal of Cell Science·Rachael C L SmithOwen J Sansom
Apr 10, 2019·Trends in Cancer·Samantha L Schuster, Andrew C Hsieh
Jul 18, 2021·Human Mutation·Cristina Perez-BecerrilMiriam J Smith

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