Upstream open reading frames: new players in the landscape of cancer gene regulation

Abstract

The translation of RNA by ribosomes represents a central biological process and one of the most dysregulated processes in cancer. While translation is traditionally thought to occur exclusively in the protein-coding regions of messenger RNAs (mRNAs), recent transcriptome-wide approaches have shown abundant ribosome activity across diverse stretches of RNA transcripts. The most common type of this kind of ribosome activity occurs in gene leader sequences, also known as 5′ untranslated regions (UTRs) of the mRNA, that precede the main coding sequence. Translation of these upstream open reading frames (uORFs) is now known to occur in upwards of 25% of all protein-coding genes. With diverse functions from RNA regulation to microprotein generation, uORFs are rapidly igniting a new arena of cancer biology, where they are linked to cancer genetics, cancer signaling, and tumor-immune interactions. This review focuses on the contributions of uORFs and their associated 5′UTR sequences to cancer biology.

Editorial: Translational control in cancer

“…The uORFs are regions upstream of the main protein coding sequence where ribosomes can assemble to produce distinct peptides or affect translation initiation of the canonical ORF. Dasgupta and Prensner describe how uORFs and their 5′UTR sequences can modulate oncogenic signaling and tumor-immune interactions through these types of mechanisms ( 9 ). RNA G-quadruplexes are widely-distributed, non-canonical, four-stranded structures that control multiple steps of post-transcriptional and translational gene expression regulation.…”