Hann, S. R., King, M. W., Bentley, D. L., Anderson, C. W. & Eisenman, R. N. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas. Cell 52, 185-195
The c-myc gene comprises three exons with a single large AUG-initiated open reading frame extending from exon 2 through exon 3. Exon 1 lacks any AUG codons. Cells from a wide range of species produce two c-myc proteins that, while highly related, do not appear to arise from posttranslational interconversion. To understand the origin of the two proteins, we mapped them and analyzed the in vitro protein-coding capacity of c-myc cDNAs. Our findings show that the two proteins are derived from alternative translational initiations at the exon 2 AUG and at a non-AUG codon near the 3' end of exon 1, resulting in the production of proteins with distinct N termini. In Burkitt's lymphomas, the removal or specific mutation of exon 1 in c-myc translocations correlates with suppression of synthesis of the larger protein, and thus may contribute to the oncogenic activation of c-myc.
"RAN translation occurs independent of the canonical AUG codon and has been demonstrated in vitro and in vivo (Hann et al., 1988; Kozak, 1989; Peabody, 1989). Recent studies have confirmed that despite the absence of an upstream AUG codon, RAN translation of repeat expansion tracks can occur in all 3 0 reading frames from both the sense and antisense transcripts (SCA8 example, Fig. 3). "
[Show abstract][Hide abstract] ABSTRACT: RNA-mediated mechanisms of disease pathogenesis in neurological disorders have been recognized in the context of certain repeat expansion disorders. This RNA-initiated neurodegeneration may play a more pervasive role in disease pathology beyond the classic dynamic mutation disorders. Here, we review the mechanisms of RNA toxicity and aberrant RNA processing that have been implicated in ageing-related neurological disorders. We focus on diseases with aberrant sequestration of RNA-binding proteins, bi-directional transcription, aberrant translation of repeat expansion RNA transcripts (repeat-associated non-ATG (RAN) translation), and the formation of pathological RNA:DNA secondary structure (R-loop). It is likely that repeat expansion disorders arise from common mechanisms caused by the repeat expansion mutations. However, the context of the repeat expansion determines the specific molecular consequences, leading to clinically distinct disorders.
Journal of Genetics and Genomics 09/2014; 41(9):473-484. DOI:10.1016/j.jgg.2014.08.003 · 3.59 Impact Factor
"Our initial investigation into the origin of these three Caytaxin isoforms revealed that Caytaxin is one of few proteins consisting of multiple isoforms that are generated by different methionine translational start sites (Fig. 3C & D). This phenomenon is more often found in yeast proteins as well as in transcription factors and oncogenes  such as the cell-regulation gene c-Myc, which encodes three c-Myc protein isoforms originating from non-AUG and AUG codons , . We identified two independent AUG start codons directly responsible for the production of the two larger Caytaxin isoforms. "
[Show abstract][Hide abstract] ABSTRACT: Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt) rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit) (jittery) and Atcay(swd) (sidewinder) mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes) (hesitant) line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.
PLoS ONE 11/2012; 7(11):e50570. DOI:10.1371/journal.pone.0050570 · 3.23 Impact Factor
"The extensive upstream non-AUG initiation we observe is likely to regulate protein synthesis from specific transcripts in response to global changes in initiation. It is also regulated during EB formation, suggesting a global link with growth and proliferation, and is involved in the synthesis of functional proteins, including the well-studied oncogene and pluripotency factor Myc (Hann et al., 1988). More broadly, it has been implicated in the production of peptides for immune surveillance (Malarkannan et al., 1999), and additional roles will likely emerge as we understand more about which non-AUG codons are used and how this selection is regulated. "
[Show abstract][Hide abstract] ABSTRACT: The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. Here we present a suite of techniques, based on ribosome profiling (the deep sequencing of ribosome-protected mRNA fragments), to provide genome-wide maps of protein synthesis as well as a pulse-chase strategy for determining rates of translation elongation. We exploit the propensity of harringtonine to cause ribosomes to accumulate at sites of translation initiation together with a machine learning algorithm to define protein products systematically. Analysis of translation in mouse embryonic stem cells reveals thousands of strong pause sites and unannotated translation products. These include amino-terminal extensions and truncations and upstream open reading frames with regulatory potential, initiated at both AUG and non-AUG codons, whose translation changes after differentiation. We also define a class of short, polycistronic ribosome-associated coding RNAs (sprcRNAs) that encode small proteins. Our studies reveal an unanticipated complexity to mammalian proteomes.
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