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

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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 platinumbased chemotherapy.

Original language	English
Pages (from-to)	1891-1896
Number of pages	6
Journal	Genes and development
Volume	29
Issue number	18
DOIs	https://doi.org/10.1101/gad.261867.115
Publication status	Published - 15 Sept 2015

Keywords

DNA damage repair
ERCC5
Protein synthesis
uORF

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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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{21f232365a2f400b9de095ed212c623d,

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",

publisher = "Cold Spring Harbor Laboratory Press",

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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, no. 18, pp. 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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DO - 10.1101/gad.261867.115

M3 - Article

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AN - SCOPUS:84941954686

SN - 0890-9369

VL - 29

SP - 1891

EP - 1896

JO - Genes and development

JF - Genes and development

IS - 18

ER -

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

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Keywords

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