scholarly journals Translation initiation in cancer at a glance

2021 ◽  
Vol 134 (1) ◽  
pp. jcs248476
Author(s):  
Rachael C. L. Smith ◽  
Georgios Kanellos ◽  
Nikola Vlahov ◽  
Constantinos Alexandrou ◽  
Anne E. Willis ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Ribosomal Subunits ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Tumour Formation ◽  
Multistep Process ◽  
Proliferation And Metastasis ◽  
Regulated Gene Expression ◽  
And Function

ABSTRACTCell division, differentiation and function are largely dependent on accurate proteome composition and regulated gene expression. To control this, protein synthesis is an intricate process governed by upstream signalling pathways. Eukaryotic translation is a multistep process and can be separated into four distinct phases: initiation, elongation, termination and recycling of ribosomal subunits. Translation initiation, the focus of this article, is highly regulated to control the activity and/or function of eukaryotic initiation factors (eIFs) and permit recruitment of mRNAs to the ribosomes. In this Cell Science at a Glance and accompanying poster, we outline the mechanisms by which tumour cells alter the process of translation initiation and discuss how this benefits tumour formation, proliferation and metastasis.

scholarly journals Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1984
Author(s):  
Qin Chen ◽  
Bo Yang ◽  
Norbert Nass ◽  
Christoph Schatz ◽  
Johannes Haybaeck
Keyword(s):  
Translation Initiation ◽  
Protein Biosynthesis ◽  
Regulatory Mechanisms ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Translation Initiation Factors ◽  
Eukaryotic Translation Initiation ◽  
Eukaryotic Translation Initiation Factors ◽  
The Relationship

Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC.

scholarly journals The Jigsaw Puzzle of mRNA Translation Initiation in Eukaryotes: A Decade of Structures Unraveling the Mechanics of the Process

2018 ◽  
Vol 47 (1) ◽  
pp. 125-151 ◽  
Author(s):  
Yaser Hashem ◽  
Joachim Frank
Keyword(s):  
Structural Biology ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Start Codon ◽  
Jigsaw Puzzle ◽  
Reading Frame ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Initiation Process

Translation initiation in eukaryotes is a highly regulated and rate-limiting process. It results in the assembly and disassembly of numerous transient and intermediate complexes involving over a dozen eukaryotic initiation factors (eIFs). This process culminates in the accommodation of a start codon marking the beginning of an open reading frame at the appropriate ribosomal site. Although this process has been extensively studied by hundreds of groups for nearly half a century, it has been only recently, especially during the last decade, that we have gained deeper insight into the mechanics of the eukaryotic translation initiation process. This advance in knowledge is due in part to the contributions of structural biology, which have shed light on the molecular mechanics underlying the different functions of various eukaryotic initiation factors. In this review, we focus exclusively on the contribution of structural biology to the understanding of the eukaryotic initiation process, a long-standing jigsaw puzzle that is just starting to yield the bigger picture.

scholarly journals A Leaderless mRNA Can Bind to Mammalian 80S Ribosomes and Direct Polypeptide Synthesis in the Absence of Translation Initiation Factors

2006 ◽  
Vol 26 (8) ◽  
pp. 3164-3169 ◽  
Author(s):  
Dmitri E. Andreev ◽  
Ilya M. Terenin ◽  
Yan E. Dunaevsky ◽  
Sergei E. Dmitriev ◽  
Ivan N. Shatsky
Keyword(s):  
Translation Initiation ◽  
Striking Similarity ◽  
Alternative Mode ◽  
80S Ribosome ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Leaderless Mrna ◽  
Translation Initiation Factors ◽  
Polypeptide Synthesis ◽  
Multistep Process

ABSTRACT Translation initiation in eukaryotic cells is known to be a complex multistep process which involves numerous protein factors. Here we demonstrate that leaderless mRNAs with initiator Met-tRNA can bind directly to 80S mammalian ribosomes in the absence of initiation factors and that the complexes thus formed are fully competent for the subsequent steps of polypeptide synthesis. We show that the canonical 48S pathway of eukaryotic translation initiation has no obvious advantage over the 80S pathway of translation initiation on leaderless mRNAs and suggest that, in the presence of competing mRNAs containing a leader, the latter mechanism will be preferred. The direct binding of the leaderless mRNA to the 80S ribosome was precluded when such an mRNA was supplied with a 5′ leader, irrespective of whether it was in a totally single-stranded conformation or was prone to base pairing. The striking similarity between the mechanisms of binding of leaderless mRNAs with mammalian 80S or bacterial 70S ribosomes gives support to the idea that the alternative mode of translation initiation used by leaderless mRNAs represents a relic from early steps in the evolution of the translation apparatus.

scholarly journals Leaderless mRNAs Bind 70S Ribosomes More Strongly than 30S Ribosomal Subunits in Escherichia coli

2002 ◽  
Vol 184 (23) ◽  
pp. 6730-6733 ◽  
Author(s):  
Sean M. O'Donnell ◽  
Gary R. Janssen
Keyword(s):  
Escherichia Coli ◽  
Translation Initiation ◽  
Primer Extension ◽  
Ribosomal Subunits ◽  
Ribosome Binding ◽  
Initiation Factors ◽  
Translation Initiation Factors

ABSTRACT By primer extension inhibition assays, 70S ribosomes bound with higher affinity, or stability, than did 30S subunits to leaderless mRNAs containing AUG or GUG start codons. Addition of translation initiation factors affected ribosome binding to leaderless mRNAs. Our results suggest that translation of leaderless mRNAs might initiate through a pathway involving 70S ribosomes or 30S subunits lacking IF3.

scholarly journals Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

2021 ◽  
Vol 118 (6) ◽  
pp. e2017715118
Author(s):  
Christopher P. Lapointe ◽  
Rosslyn Grosely ◽  
Alex G. Johnson ◽  
Jinfan Wang ◽  
Israel S. Fernández ◽  
...  
Keyword(s):  
Single Molecule ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Start Codon ◽  
Messenger Rnas ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
40S Ribosomal Subunit ◽  
Eukaryotic Translation Initiation Factors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-CoV that recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome. We demonstrate biochemically that NSP1 inhibits translation of model human and SARS-CoV-2 messenger RNAs (mRNAs). NSP1 specifically binds to the small (40S) ribosomal subunit, which is required for translation inhibition. Using single-molecule fluorescence assays to monitor NSP1–40S subunit binding in real time, we determine that eukaryotic translation initiation factors (eIFs) allosterically modulate the interaction of NSP1 with ribosomal preinitiation complexes in the absence of mRNA. We further elucidate that NSP1 competes with RNA segments downstream of the start codon to bind the 40S subunit and that the protein is unable to associate rapidly with 80S ribosomes assembled on an mRNA. Collectively, our findings support a model where NSP1 proteins from viruses in at least two subgenera of beta-CoVs associate with the open head conformation of the 40S subunit to inhibit an early step of translation, by preventing accommodation of mRNA within the entry channel.

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