A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy
Author(s)Somers, Joanna; Wilson, Lindsay A.; Kilday, John-Paul; Horvilleur, Emilie; Cobbold, Laura C.; Kondrashov, Alexander; Grill, Jacques; Grundy, Richard G.; Bushell, Martin; Willis, Anne E.; Poyry, Tuija A. A.; Puget, Stephanie; Knight, John R. P.; Cannell, Ian G.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT
Genes & Development
Cold Spring Harbor Laboratory Press
Somers, Joanna, Lindsay A. Wilson, John-Paul Kilday, Emilie Horvilleur, Ian G. Cannell, Tuija A.A. Poyry, Laura C. Cobbold, et al. “A Common Polymorphism in the 5′ UTR of ERCC5 Creates an Upstream ORF That Confers Resistance to Platinum-Based Chemotherapy.” Genes Dev. 29, no. 18 (September 3, 2015): 1891–1896.
Final published version