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 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.
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Joanna
J
Somers
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Lindsay A
LA
Wilson
Children's Brain Tumour Research Centre, The Medical School, University of Nottingham, Nottingham NG7 2UH, United Kingdom;
John-Paul
JP
Kilday
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Emilie
E
Horvilleur
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Ian G
IG
Cannell
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Tuija A A
TA
Pöyry
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Laura C
LC
Cobbold
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom;
Alexander
A
Kondrashov
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
John R P
JR
Knight
Departement de Neurochirugie Pédiatrique, Hôpital Necker, University Paris V Descartes, 75006 Paris, France;
Stéphanie
S
Puget
Department of Pediatric and Adolescent Oncology, Institut Gustave Roussy, 94805 Villejuif, France.
Jacques
J
Grill
Children's Brain Tumour Research Centre, The Medical School, University of Nottingham, Nottingham NG7 2UH, United Kingdom;
Richard G
RG
Grundy
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Martin
M
Bushell
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
Anne E
AE
Willis
D020121:5' Untranslated Regions / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism*; D004806:Ependymoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000099250:DNA Excision Repair Protein ERCC-5
D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C109198:CIB1 protein, human
DNA damage repair; ERCC5; protein synthesis; uORF