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

Abstract

The gene expression pathway from DNA sequence to functional protein is not as straightforward as simple depictions of the Central Dogma might suggest. Each step is highly regulated, with complex and only partially understood molecular mechanisms at play. Translation is one step where the “one gene-one protein” paradigm breaks down, as often a single mature eukaryotic mRNA leads to more than one protein product. One way this occurs is through translation reinitiation, in which a ribosome starts making protein from one initiation site, translates until it terminates at a stop codon, but then escapes normal recycling steps and subsequently reinitiates at a different downstream site. This process is now recognized as both important and widespread, but we are only beginning to understand the interplay of factors involved in termination, recycling, and initiation that cause reinitiation events. There appear to be several ways to subvert recycling to achieve productive reinitiation, different types of stresses or signals that trigger this process, and the mechanism may depend in part on where the event occurs in the body of an mRNA. This perspective reviews the unique characteristics and mechanisms of reinitiation events, highlights the similarities and differences between the three major scenarios of reinitiation, and raises outstanding questions that are promising avenues for future research.

Escaping from CRISPR–Cas-mediated knockout: the facts, mechanisms, and applications

“…The distance between PTC and the nearby AUG may be a key determinant for the reinitiation efficiency. If the translation reinitiation starts from an in-frame AUG, an N-terminal truncated protein will be produced, which may maintain certain functionality [ 47 , 48 ].…”

Host-like RNA Elements Regulate Virus Translation

“…In contrast, an upstream AUG preceding the main ORF start codon can be in an overlapping ORF, with 2 further subclasses: out-of-frame overlapping uORFs (oORFs), the stop codons of which are downstream of main ORF AUGs and in different reading frames, and N-terminal extensions, which are basically overlapping uORFs in-frame with the main ORF [ 140 , 141 , 142 , 143 , 144 ] ( Figure 1 ). The downstream CDS can be engaged by the re-initiating PIC only when the translated uORFs do not overlap with CDSs [ 145 ], or in special cases through a TURBS (termination upstream ribosome binding site) RNA element at the end of the preceding ORF (reviewed in [ 145 , 146 ], see below) ( Figure 1 ). In addition to leaky scanning, bi-directional scanning of the PIC between closely spaced start codons, as in oORFs, can influence start site selection [ 147 , 148 ].…”

“…In these cases, the uORF stop codon and downstream ORF start codon are in close proximity, out-of-frame, or overlap in consecutive nucleotides. The viral TURBS regulates reinitiation through base-pairing with 18S rRNA and tethering of the post-termination 40S subunit (reviewed in [ 145 , 146 ]). It has been suggested that uORFs in the 5′UTR regulate translation of cellular SLAMF1 mRNA utilizing a TURBS-like element, highlighting shared strategies in eukaryotic translational control [ 170 ].…”

The Roles of eIF4G2 in Leaky Scanning and Reinitiation on the Human Dual-Coding POLG mRNA

“…Reinitiation is a poorly understood process [33][34][35][36] that includes (a) the transition from the post-termination state to the scanning-competent state, (b) the reacquisition of eIF2, and (c) the scanning itself. The reinitiated scanning ribosomes can potentially interfere with ribosomes translating a downstream ORF (POLGARF in our case), as they do in the case of eIF4G2-dependent leaky scanning.…”