Investigating the role of mRNA capping enzyme in C-MYC function

  • Olivia Lombardi

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

C-MYC is a transcription factor and a potent driver of many human cancers. In addition to regulating transcription, C-MYC promotes formation of the mRNA cap which is important for transcript maturation and translation. However, the mechanistic details of C-MYC-dependent mRNA capping are not fully understood. Since anti-cancer strategies to directly target the C-MYC protein have had limited success, enzymatic co-factors or effectors of C-MYC present attractive alternatives for therapeutic intervention of C-MYC-driven cancers. mRNA capping enzyme (CE) initiates mRNA cap formation by catalysing the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide. The involvement of CE in C-MYC-dependent mRNA capping and C-MYC function has not yet been explored. Therefore, I sought to determine whether C-MYC regulates CE, and whether CE is required for C-MYC function.
I found that C-MYC promotes CE recruitment to RNA polymerase II (RNA pol II) transcription complexes and to regions proximal to transcription start sites on chromatin. Consistently, C-MYC increases RNA pol II-associated CE activity. Interestingly, cells driven by C-MYC are highly dependent on CE for C-MYC-induced target gene expression and cell transformation, but only when C-MYC is overexpressed; C-MYC-independent cells or cells retaining normal control of C-MYC expression are insensitive to CE inhibition. C-MYC expression is also dependent on CE. Taken together, I present a bidirectional regulatory relationship between C-MYC and CE which is potentially therapeutically relevant. Studies here strongly suggest that inhibiting CE is an attractive
strategy to selectively target cancer cells which have acquired deregulated C-MYC.
Date of Award2017
LanguageEnglish
Awarding Institution
  • University of Dundee
Add any sponsors of the thesis researchBiotechnology and Biological Sciences Research Council
SupervisorVictoria Cowling (Supervisor)

Keywords

  • C-MYC
  • mRNA capping
  • Transcription
  • RNA polymerase II
  • Capping enzyme
  • Breast cancer
  • Oncogene

Cite this

Investigating the role of mRNA capping enzyme in C-MYC function
Lombardi, O. (Author). 2017

Student thesis: Doctoral ThesisDoctor of Philosophy