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

Genes Dev. 2015 Sep 15;29(18):1891-6. doi: 10.1101/gad.261867.115. Epub 2015 Sep 3.

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.

Keywords: DNA damage repair; ERCC5; protein synthesis; uORF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Calcium-Binding Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • DNA Damage
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm / genetics*
  • Endonucleases / genetics*
  • Endonucleases / metabolism*
  • Ependymoma / drug therapy
  • Ependymoma / genetics*
  • Ependymoma / mortality
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Open Reading Frames / genetics*
  • Polymorphism, Genetic / genetics*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*

Substances

  • 5' Untranslated Regions
  • Antineoplastic Agents
  • CIB1 protein, human
  • Calcium-Binding Proteins
  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Endonucleases
  • Cisplatin