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Emerging links between initiation of translation and human diseases
1Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, New Jersey 08854, USA. kozakma@umdnj.edu
Abstract:
Some diseases are caused by mutations that perturb the initiation step of translation by changing the context around the AUG(START) codon or introducing upstream AUG codons. The scanning mechanism provides a framework for understanding the effects of these and other structural changes in mRNAs derived from oncogenes, tumor suppressor genes, and other key regulatory genes. In mRNAs from mutated as well as normal genes, translation sometimes initiates from an internal AUG codon. Sanctioned mechanisms that allow this, including leaky scanning and reinitiation, are discussed. Thrombopoietin mRNA is an example in which translation normally initiates from an internal position via an inefficient reinitiation mechanism. Mutations that restructure this mRNA in ways that elevate production of thrombopoietin cause hereditary thrombocythemia, demonstrating that some mRNAs are designed deliberately with upstream AUG codons to preclude efficient translation and thus to prevent harmful overproduction of potent proteins. While upstream AUG codons in certain mRNAs thus play an important regulatory role, the frequency of upstream AUG codons tends to be exaggerated when cDNA sequences are compiled and analyzed. Because the discovery of mutations that perturb translation usually begins with cDNA analysis, some misunderstandings vis-a-vis the interpretation of cDNA sequences are discussed.
Insights
Mutations affecting translation initiation can cause diseases. Some mRNAs use upstream AUG codons to prevent harmful protein overproduction, a regulatory mechanism sometimes misinterpreted in cDNA analysis.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Translation initiation is crucial for gene expression and can be disrupted by mutations.
- The scanning model explains how ribosomes find the start codon (AUG) on messenger RNA (mRNA).
- Aberrant translation initiation is linked to diseases, including those involving oncogenes and tumor suppressor genes.
Purpose of the Study:
- To explore how mutations and mRNA structures affect translation initiation.
- To discuss mechanisms like leaky scanning and reinitiation that allow internal AUG initiation.
- To highlight the regulatory role of upstream AUG codons and potential misinterpretations in cDNA analysis.
Main Methods:
- Analysis of mRNA structures and translation initiation mechanisms.
- Review of the scanning model and its implications.
- Case study of thrombopoietin mRNA and hereditary thrombocythemia.
Main Results:
- Mutations altering the context of AUG codons or introducing upstream AUGs can perturb translation initiation.
- Internal AUG initiation occurs via mechanisms like leaky scanning and reinitiation.
- Thrombopoietin mRNA utilizes inefficient reinitiation, and its mutations cause hereditary thrombocythemia.
- Upstream AUG codons can serve a regulatory role by limiting protein production.
Conclusions:
- Understanding translation initiation is key to deciphering disease mechanisms.
- Upstream AUG codons are important regulatory elements, preventing protein overproduction.
- Careful interpretation of cDNA sequences is necessary to avoid misunderstandings regarding upstream AUG codons.