More than just scanning: the importance of cap-independent mRNA translation initiation for cellular stress response and cancer

Abstract

The scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds at the cap structure at the 5' end of the mRNA and scans the 5' untranslated region (5'UTR) until an initiation codon is found. However, under conditions that impair canonical cap-dependent translation, the synthesis of some proteins is kept by alternative mechanisms that are required for cell survival and stress recovery. Alternative modes of translation initiation include cap- and/or scanning-independent mechanisms of ribosomal recruitment. In most cap-independent translation initiation events there is a direct recruitment of the 40S ribosome into a position upstream, or directly at, the initiation codon via a specific internal ribosome entry site (IRES) element in the 5'UTR. Yet, in some cellular mRNAs, a different translation initiation mechanism that is neither cap- nor IRES-dependent seems to occur through a special RNA structure called cap-independent translational enhancer (CITE). Recent evidence uncovered a distinct mechanism through which mRNAs containing N -methyladenosine (mA) residues in their 5'UTR directly bind eukaryotic initiation factor 3 (eIF3) and the 40S ribosomal subunit in order to initiate translation in the absence of the cap-binding proteins. This review focuses on the important role of cap-independent translation mechanisms in human cells and how these alternative mechanisms can either act individually or cooperate with other cis-acting RNA regulons to orchestrate specific translational responses triggered upon several cellular stress states, and diseases such as cancer. Elucidation of these non-canonical mechanisms reveals the complexity of translational control and points out their potential as prospective novel therapeutic targets.

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

“…2b). Indeed, most proposed cellular IRESs reside in mRNAs that rely on internal initiation for sustained translation in conditions of stress, mitosis or apoptosis, which reduce global cap-dependent translation (reviewed in REFS 100–105). The first cellular IRES, for example, was discovered in the mRNA encoding immunoglobulin heavy chain-binding protein (BiP; also known as GRP78), a stress-induced chaperone 106 .…”

“…These mRNAs mostly encode transcription factors, growth factors and transporters 105 . Nevertheless, after decades of work, few examples have been well characterized.…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Finally, in a process catalyzed by eIF5B, the large 60S ribosomal subunit joins the PIC, leading to dissociation of several of the remaining initiation factors, and formation of a functional 80S initiation complex (reviewed in Hinnebusch, 2014; Jackson et al, 2010; Sonenberg and Hinnebusch, 2009). In addition to cap-dependent translation, a small subset of eukaryotic mRNAs undergo translational initiation through alternative means, such as by ribosome recruitment to an internal ribosome entry site (IRES) (recently reviewed in Lacerda et al, 2017). …”

A New Way to Discover IRESs in Pathology or Stress Conditions? Harnessing Latest High‐Throughput Technologies

“…Investigations have indicated that abnormal cellular IRES function contributes to cancer, Charcot–Marie–Tooth disease, Alzheimer's disease, and some other disorders . Some key genes contributing to the disease process are directly regulated by IRES elements.…”

“…In disease development, IRES may be activated to facilitate APP mRNA translation. Similarly, in cancers, IRES elements have been widely reported to play important roles in both carcinogenesis and responses to drug treatment . However, there is still no suitable method to systematically identify cellular IRES elements and their activity directly from tissues.…”