![]() ![]() First of all, IRES structural forms within 5ʹ untranslated regions (UTRs) can interact with RNA-binding proteins known as IRES trans-acting factors (ITAFs) to remodel their structures, thus opening the hindrance to ribosome recruitment. Although cellular IRESs generally show lower structural similarities to one another and are less structured than viral IRESs, they can be roughly categorized into three different functional genres with some identifiable patterns ( 11). They usually bare sequence or structural motifs that can recruit the translation machinery to initiate the translation initiation stage ( 10). Therefore, it is crucial to investigate cellular IRES elements, thus unraveling the nature of cellular stress responses and tumor therapeutic targets.Ĭurrently known cellular IRES elements are mostly found in genes involved in stress, mitosis or apoptosis ( 9). Cellular IRES elements are now known to be closely related to selective cellular protein synthesis under stress and physiopathological conditions ( 7) and can have profound effects on human tumor cells ( 8). Since then, scientists have found different IRES elements in other viruses ( 5) and in cellular genes ( 6). IRES-mediated translational initiation was first discovered in poliovirus ( 4). However, when facing stressed environments or other physiological challenges, cellular translation can be initiated in a cap-independent manner via the help of the internal ribosome entry site (IRES) elements. Under normal situations, eukaryotic canonical cap-dependent translation initiation is started by the pre-initiation complex formed with initiators tRNA, eIF2, eIF3 and eIF4 to scan for the start codon. For eukaryotes, the complex phase of cellular translation initiation can be categorized into two different types: cap-dependent translation initiation and cap-independent translation initiation ( 3). Importantly, translation initiation is widely considered to be a vital step in translational regulation ( 2). In summary, Human IRES Atlas integrates putative IRES elements and translation initiation–related experiments for better usage of these data and deduction of mechanism hypotheses.Ĭells in proliferation adapt their metabolism to environmental stimuli through the regulation of protein synthesis, and translational regulation can provide instant protein level adjustment for handling sudden environmental changes and stress responses ( 1). Researchers can easily search/browse an IRES of interest using the web interface and deduce testable mechanism hypotheses of human IRES-driven translation initiation based on the integrated results. Moreover, an easy-to-use interface and an IRES–translation initiation interaction map for each gene transcript were implemented to help understand the interactions between IRESs and translation initiation–related features. ![]() Three functional tests (conservation, structural RNA–protein scores and conditional translation efficiency) were devised to evaluate the functionality of the identified putative IRESs. Then, we collected eight genres of translation initiation–related features to help study the potential molecular mechanisms of each of the putative IRESs. First, currently available and suitable IRES prediction tools (IRESfinder, PatSearch and IRESpy) were used to obtain transcriptome-wide human IRESs. In this research, we constructed the Human IRES Atlas database for a comprehensive understanding of cellular IRESs in humans. However, three problems make it hard to understand transcriptome-wide cellular IRES-mediated translation initiation mechanisms: (i) complex interplay between IRESs and other translation initiation–related information, (ii) reliability issue of in silico cellular IRES investigation and (iii) labor-intensive in vivo IRES identification. It is now known that cap-independent translation initiation facilitated by internal ribosome entry sites (IRESs) is vital in selective cellular protein synthesis under stress and different physiological conditions. ![]()
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