Near-Cognate Codons Contribute Complexity to Translation Regulation

Abstract

The interplay between translation initiation, modification of translation initiation factors, and selection of start sites on mRNA for protein synthesis can play a regulatory role in the cellular response to stress, development, and cell fate in eukaryotic species by shaping the proteome. As shown by Ivanov et al. (mBio 8:e00844-17, 2017, https://doi.org/10.1128/mBio.00844-17), in the filamentous fungus Neurospora crassa, both upstream open reading frames (uORFs) and near-cognate start codons negatively or positively regulate the translation of the transcription factor CPC1 and production of CPC1 isoforms, which mediate the cellular response to amino acid starvation. Dissecting the physiological roles that differentiate cellular choice of translation initiation is an important parameter to understanding mechanisms that determine cell fate via gene regulation and protein synthesis.

Principles, mechanisms, and biological implications of translation termination–reinitiation

“…CUG) undergo reinitiation at a frequency of ~45% or less compared to wildtype (Luttermann and Meyers 2007). Reinitiation at a main ORF following a round of translation at a uORF is less efficient at near-cognate start codons, which subsequently affects the levels of gene expression (Glass 2017). In the context of reinitiation after at PTC, mutating the downstream AUG can increase sensitivity to NMD (Neu-Yilik et al 2011), indicating fewer productive downstream translation events.…”