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

Joanna Somers; Lindsay A. Wilson; John Paul Kilday; Emilie Horvilleur; Ian G. Cannell; Tuija A.A. Pöyry; Laura C. Cobbold; Alexander Kondrashov; John R.P. Knight; Stéphanie Puget; Jacques Grill; Richard G. Grundy; Martin Bushell; Anne E. Willis

doi:10.1101/gad.261867.115

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

Joanna Somers, Lindsay A. Wilson, John Paul Kilday, Emilie Horvilleur, Ian G. Cannell, Tuija A.A. Pöyry, Laura C. Cobbold, Alexander Kondrashov, John R.P. Knight, Stéphanie Puget, Jacques Grill, Richard G. Grundy, Martin Bushell, Anne E. Willis

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Résumé

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 platinumbased chemotherapy.

langue originale	Anglais
Pages (de - à)	1891-1896
Nombre de pages	6
journal	Genes and Development
Volume	29
Numéro de publication	18
Les DOIs	https://doi.org/10.1101/gad.261867.115
état	Publié - 15 sept. 2015

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10.1101/gad.261867.115

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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., & Willis, A. E. (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), 1891-1896. https://doi.org/10.1101/gad.261867.115

@article{c0b6cc057bbd4ade994464cd74473fea,

title = "A common polymorphism in the 5{\textquoteright} UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy",

abstract = "We show that a common polymorphic variant in the ERCC5 5{\textquoteright} 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{\textquoteright} noncoding mRNA element influences individuals{\textquoteright} responses to platinumbased chemotherapy.",

keywords = "DNA damage repair, ERCC5, Protein synthesis, uORF",

author = "Joanna Somers and Wilson, {Lindsay A.} and Kilday, {John Paul} and Emilie Horvilleur and Cannell, {Ian G.} and P{\"o}yry, {Tuija A.A.} and Cobbold, {Laura C.} and Alexander Kondrashov and Knight, {John R.P.} and St{\'e}phanie Puget and Jacques Grill and Grundy, {Richard G.} and Martin Bushell and Willis, {Anne E.}",

note = "Publisher Copyright: {\textcopyright} 2015 Somers et al.",

year = "2015",

month = sep,

day = "15",

doi = "10.1101/gad.261867.115",

language = "English",

volume = "29",

pages = "1891--1896",

journal = "Genes and Development",

issn = "0890-9369",

number = "18",

}

Somers, J, Wilson, LA, Kilday, JP, Horvilleur, E, Cannell, IG, Pöyry, TAA, Cobbold, LC, Kondrashov, A, Knight, JRP, Puget, S, Grill, J, Grundy, RG, Bushell, M & Willis, AE 2015, 'A common polymorphism in the 5’ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy', Genes and Development, VOL. 29, Numéro 18, p. 1891-1896. https://doi.org/10.1101/gad.261867.115

TY - JOUR

T1 - A common polymorphism in the 5’ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy

AU - Somers, Joanna

AU - Wilson, Lindsay A.

AU - Kilday, John Paul

AU - Horvilleur, Emilie

AU - Cannell, Ian G.

AU - Pöyry, Tuija A.A.

AU - Cobbold, Laura C.

AU - Kondrashov, Alexander

AU - Knight, John R.P.

AU - Puget, Stéphanie

AU - Grill, Jacques

AU - Grundy, Richard G.

AU - Bushell, Martin

AU - Willis, Anne E.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - 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 platinumbased chemotherapy.

AB - 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 platinumbased chemotherapy.

KW - DNA damage repair

KW - ERCC5

KW - Protein synthesis

KW - uORF

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U2 - 10.1101/gad.261867.115

DO - 10.1101/gad.261867.115

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AN - SCOPUS:84941954686

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JO - Genes and Development

JF - Genes and Development

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