期刊
GENES & DEVELOPMENT
卷 29, 期 18, 页码 1891-1896出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.261867.115
关键词
DNA damage repair; ERCC5; protein synthesis; uORF
资金
- Cancer Research UK
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Societe Francaise des Cancers de l'Enfant/Enfants et Sante
- Etoile de Martin
- Fondation Carrefour
- Joe Foote Foundation
- BBSRC [BB/F02326X/2] Funding Source: UKRI
- MRC [MC_EX_G0902052, MC_UP_A600_1023, MC_UP_A600_1024] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F02326X/2] Funding Source: researchfish
- Medical Research Council [MC_UP_A600_1023, MC_EX_G0902052, MC_UP_A600_1024] Funding Source: researchfish
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.
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