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

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...

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Autores principales: Somers, Joanna, Wilson, Lindsay A., Kilday, John-Paul, Horvilleur, Emilie, Cannell, Ian G., Pöyry, Tuija A.A., Cobbold, Laura C., Kondrashov, Alexander, Knight, John R.P., Puget, Stéphanie, Grill, Jacques, Grundy, Richard G., Bushell, Martin, Willis, Anne E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Research Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579346/
https://www.ncbi.nlm.nih.gov/pubmed/26338418
http://dx.doi.org/10.1101/gad.261867.115
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author Somers, Joanna
Wilson, Lindsay A.
Kilday, John-Paul
Horvilleur, Emilie
Cannell, Ian G.
Pöyry, Tuija A.A.
Cobbold, Laura C.
Kondrashov, Alexander
Knight, John R.P.
Puget, Stéphanie
Grill, Jacques
Grundy, Richard G.
Bushell, Martin
Willis, Anne E.
author_facet Somers, Joanna
Wilson, Lindsay A.
Kilday, John-Paul
Horvilleur, Emilie
Cannell, Ian G.
Pöyry, Tuija A.A.
Cobbold, Laura C.
Kondrashov, Alexander
Knight, John R.P.
Puget, Stéphanie
Grill, Jacques
Grundy, Richard G.
Bushell, Martin
Willis, Anne E.
author_sort Somers, Joanna
collection PubMed
description 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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spelling pubmed-45793462015-09-29 A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy Somers, Joanna Wilson, Lindsay A. Kilday, John-Paul Horvilleur, Emilie Cannell, Ian G. Pöyry, Tuija A.A. Cobbold, Laura C. Kondrashov, Alexander Knight, John R.P. Puget, Stéphanie Grill, Jacques Grundy, Richard G. Bushell, Martin Willis, Anne E. Genes Dev Research Communication 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. Cold Spring Harbor Laboratory Press 2015-09-15 /pmc/articles/PMC4579346/ /pubmed/26338418 http://dx.doi.org/10.1101/gad.261867.115 Text en © 2015 Somers et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Communication
Somers, Joanna
Wilson, Lindsay A.
Kilday, John-Paul
Horvilleur, Emilie
Cannell, Ian G.
Pöyry, Tuija A.A.
Cobbold, Laura C.
Kondrashov, Alexander
Knight, John R.P.
Puget, Stéphanie
Grill, Jacques
Grundy, Richard G.
Bushell, Martin
Willis, Anne E.
A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title_full A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title_fullStr A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title_full_unstemmed A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title_short A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
title_sort common polymorphism in the 5′ utr of ercc5 creates an upstream orf that confers resistance to platinum-based chemotherapy
topic Research Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579346/
https://www.ncbi.nlm.nih.gov/pubmed/26338418
http://dx.doi.org/10.1101/gad.261867.115
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