RAN translation

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Repeat Associated Non-AUG translation, or RAN translation, is an irregular mode of mRNA translation that can occur in eukaryotic cells. [1] [2]

Contents

Mechanism

For the majority of eukaryotic messenger RNAs (mRNAs), translation initiates from a methionine-encoding AUG start codon following the molecular processes of 'cap-binding' and 'scanning' by ribosomal pre-initiation complexes (PICs). In rare exceptions, such as translation by viral IRES-containing mRNAs, 'cap-binding' and/or 'scanning' are not required for initiation, although AUG is still typically used as the first codon. RAN translation is an exception to the canonical rules as it uses variable start site selection and initiates from a non-AUG codon, but may still depend on 'cap-binding' and 'scanning'. [3]

Disease

RAN translation produces a variety of dipeptide repeat proteins by translation of expanded hexanucleotide repeats present in an intron of the C9orf72 gene. The expansion of the hexanucleotide repeats and thus accumulation of dipeptide repeat proteins are thought to cause cellular toxicity that leads to neurodegeneration in ALS disease. [4] [5] [6] [7] [8] [9]

See also

Related Research Articles

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start site.

Trinucleotide repeat disorders, a subset of microsatellite expansion diseases, are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

Ribosome shunting is a mechanism of translation initiation in which ribosomes bypass, or "shunt over", parts of the 5' untranslated region to reach the start codon. However, a benefit of ribosomal shunting is that it can translate backwards allowing more information to be stored than usual in an mRNA molecule. Some viral RNAs have been shown to use ribosome shunting as a more efficient form of translation during certain stages of viral life cycle or when translation initiation factors are scarce. Some viruses known to use this mechanism include adenovirus, Sendai virus, human papillomavirus, duck hepatitis B pararetrovirus, rice tungro bacilliform viruses, and cauliflower mosaic virus. In these viruses the ribosome is directly translocated from the upstream initiation complex to the start codon (AUG) without the need to unwind RNA secondary structures.

<span class="mw-page-title-main">Start codon</span> First codon of a messenger RNA translated by a ribosome

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids.

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

A ribosome binding site, or ribosomal binding site (RBS), is a sequence of nucleotides upstream of the start codon of an mRNA transcript that is responsible for the recruitment of a ribosome during the initiation of translation. Mostly, RBS refers to bacterial sequences, although internal ribosome entry sites (IRES) have been described in mRNAs of eukaryotic cells or viruses that infect eukaryotes. Ribosome recruitment in eukaryotes is generally mediated by the 5' cap present on eukaryotic mRNAs.

<span class="mw-page-title-main">EIF1AX</span> Protein-coding gene in humans

Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the EIF1AX gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

<span class="mw-page-title-main">SUI1</span>

In molecular biology, the single-domain protein SUI1 is a translation initiation factor often found in the fungus, Saccharomyces cerevisiae but it is also found in other eukaryotes and prokaryotes as well as archaea. It is otherwise known as Eukaryotic translation initiation factor 1 (eIF1) in eukaryotes or YciH in bacteria.

<span class="mw-page-title-main">C9orf72</span> Protein-coding gene in the species Homo sapiens

C9orf72 is a protein which in humans is encoded by the gene C9orf72.

Marilyn S. Kozak is an American professor of biochemistry at the Robert Wood Johnson Medical School. She was previously at the University of Medicine and Dentistry of New Jersey before the school was merged. She was awarded a PhD in microbiology by Johns Hopkins University studying the synthesis of the Bacteriophage MS2, advised by Daniel Nathans. In her original faculty job proposal, she sought to study the mechanism of eukaryotic translation initiation, a problem long thought to have already been solved by Joan Steitz. While in the Department of Biological Sciences at University of Pittsburgh, she published a series of studies that established the scanning model of translation initiation and the Kozak consensus sequence. Her current research interests are unknown as her last publication was in 2008.

The 43S preinitiation complex is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3, and the eIF2-Met-tRNAiMet-GTP ternary complex (eIF2-TC).

<span class="mw-page-title-main">Translation regulation by 5′ transcript leader cis-elements</span>

Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.

References

  1. ↑ Zu, T.; Gibbens, B.; Doty, N. S.; Gomes-Pereira, M.; Huguet, A.; Stone, M. D.; Margolis, J.; Peterson, M.; Markowski, T. W.; Ingram, M. A. C.; Nan, Z.; Forster, C.; Low, W. C.; Schoser, B.; Somia, N. V.; Clark, H. B.; Schmechel, S.; Bitterman, P. B.; Gourdon, G.; Swanson, M. S.; Moseley, M.; Ranum, L. P. W. (2010). "Non-ATG-initiated translation directed by microsatellite expansions". Proceedings of the National Academy of Sciences. 108 (1): 260–265. doi: 10.1073/pnas.1013343108 . ISSN   0027-8424. PMC   3017129 . PMID   21173221.
  2. ↑ Copenhaver, Gregory P.; Pearson, Christopher E. (2011). "Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities!". PLOS Genetics. 7 (3): e1002018. doi: 10.1371/journal.pgen.1002018 . ISSN   1553-7404. PMC   3053344 . PMID   21423665.
  3. ↑ Cox, Diana C.; Cooper, Thomas A. (2016). "Non-canonical RAN Translation of CGG Repeats Has Canonical Requirements". Molecular Cell. 62 (2): 155–156. doi: 10.1016/j.molcel.2016.04.004 . ISSN   1097-2765. PMID   27105111.
  4. ↑ Renoux, Abigail J.; Todd, Peter K. (2012). "Neurodegeneration the RNA way". Progress in Neurobiology. 97 (2): 173–189. doi:10.1016/j.pneurobio.2011.10.006. ISSN   0301-0082. PMC   3582174 . PMID   22079416.
  5. ↑ Strzyz, Paulina (2016). "Translation: The features of pathologic RAN translation". Nature Reviews Molecular Cell Biology. 17 (5): 264. doi: 10.1038/nrm.2016.52 . ISSN   1471-0072. S2CID   41908729.
  6. ↑ Bañez-Coronel, Monica; Ayhan, Fatma; Tarabochia, Alex D.; Zu, Tao; Perez, Barbara A.; Tusi, Solaleh Khoramian; Pletnikova, Olga; Borchelt, David R.; Ross, Christopher A.; Margolis, Russell L.; Yachnis, Anthony T.; Troncoso, Juan C.; Ranum, Laura P.W. (2015). "RAN Translation in Huntington Disease". Neuron. 88 (4): 667–677. doi:10.1016/j.neuron.2015.10.038. ISSN   0896-6273. PMC   4684947 . PMID   26590344.
  7. ↑ Kearse, Michael G.; Green, Katelyn M.; Krans, Amy; Rodriguez, Caitlin M.; Linsalata, Alexander E.; Goldstrohm, Aaron C.; Todd, Peter K. (2016). "CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins". Molecular Cell. 62 (2): 314–322. doi:10.1016/j.molcel.2016.02.034. ISSN   1097-2765. PMC   4854189 . PMID   27041225.
  8. ↑ Green, Katelyn M.; Linsalata, Alexander E.; Todd, Peter K. (2016). "RAN translation—What makes it run?". Brain Research. 1647: 30–42. doi:10.1016/j.brainres.2016.04.003. ISSN   0006-8993. PMC   5003667 . PMID   27060770.
  9. ↑ Mori, K.; Weng, S.-M.; Arzberger, T.; May, S.; Rentzsch, K.; Kremmer, E.; Schmid, B.; Kretzschmar, H. A.; Cruts, M.; Van Broeckhoven, C.; Haass, C.; Edbauer, D. (2013). "The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS". Science. 339 (6125): 1335–1338. Bibcode:2013Sci...339.1335M. doi: 10.1126/science.1232927 . ISSN   0036-8075. PMID   23393093. S2CID   32244381.


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