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      Functional Translational Readthrough: A Systems Biology Perspective

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      PLoS Genetics
      Public Library of Science

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          Abstract

          Translational readthrough (TR) has come into renewed focus because systems biology approaches have identified the first human genes undergoing functional translational readthrough (FTR). FTR creates functional extensions to proteins by continuing translation of the mRNA downstream of the stop codon. Here we review recent developments in TR research with a focus on the identification of FTR in humans and the systems biology methods that have spurred these discoveries.

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          Most cited references58

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          PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions

          Motivation: As high-throughput transcriptome sequencing provides evidence for novel transcripts in many species, there is a renewed need for accurate methods to classify small genomic regions as protein coding or non-coding. We present PhyloCSF, a novel comparative genomics method that analyzes a multispecies nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models. Results: We show that PhyloCSF's classification performance in 12-species Drosophila genome alignments exceeds all other methods we compared in a previous study. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE, and as interest grows in long non-coding RNAs, often initially recognized by their lack of protein coding potential rather than conserved RNA secondary structures. Availability and Implementation: The Objective Caml source code and executables for GNU/Linux and Mac OS X are freely available at http://compbio.mit.edu/PhyloCSF Contact: mlin@mit.edu; manoli@mit.edu
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            Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster

            Ribosomes can read through stop codons in a regulated manner, elongating rather than terminating the nascent peptide. Stop codon readthrough is essential to diverse viruses, and phylogenetically predicted to occur in a few hundred genes in Drosophila melanogaster, but the importance of regulated readthrough in eukaryotes remains largely unexplored. Here, we present a ribosome profiling assay (deep sequencing of ribosome-protected mRNA fragments) for Drosophila melanogaster, and provide the first genome-wide experimental analysis of readthrough. Readthrough is far more pervasive than expected: the vast majority of readthrough events evolved within D. melanogaster and were not predicted phylogenetically. The resulting C-terminal protein extensions show evidence of selection, contain functional subcellular localization signals, and their readthrough is regulated, arguing for their importance. We further demonstrate that readthrough occurs in yeast and humans. Readthrough thus provides general mechanisms both to regulate gene expression and function, and to add plasticity to the proteome during evolution. DOI: http://dx.doi.org/10.7554/eLife.01179.001
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              VEGF-A splicing: the key to anti-angiogenic therapeutics?

              The physiology of microvessels limits the growth and development of tumours. Tumours gain nutrients and excrete waste through growth-associated microvessels. New anticancer therapies target this microvasculature by inhibiting vascular endothelial growth factor A (VEGF-A) splice isoforms that promote microvessel growth. However, certain VEGF-A splice isoforms in normal tissues inhibit growth of microvessels. Thus, it is the VEGF-A isoform balance, which is controlled by mRNA splicing, that orchestrates angiogenesis. Here, we highlight the functional differences between the pro-angiogenic and the anti-angiogenic VEGF-A isoform families and the potential to harness the synthetic capacity of cancer cells to produce factors that inhibit, rather than aid, cancer growth.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                4 August 2016
                August 2016
                24 August 2016
                : 12
                : 8
                : e1006196
                Affiliations
                [001]University Medical Center, Department of Child and Adolescent Health, University of Göttingen, Göttingen, Germany
                University of Münster, GERMANY
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3018-6363
                Article
                PGENETICS-D-16-00364
                10.1371/journal.pgen.1006196
                4973966
                27490485
                12c77f19-156e-4d5c-ad15-a8860bc8d8de
                © 2016 Schueren, Thoms

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 1, Tables: 1, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Review
                Biology and Life Sciences
                Biochemistry
                Ribosomes
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Ribosomes
                Biology and Life Sciences
                Systems Biology
                Computer and Information Sciences
                Systems Science
                Systems Biology
                Physical Sciences
                Mathematics
                Systems Science
                Systems Biology
                Research and Analysis Methods
                Database and Informatics Methods
                Biological Databases
                Genomic Databases
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genomic Databases
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genomic Databases
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Genetic Fingerprinting and Footprinting
                Genetic Footprinting
                Research and Analysis Methods
                Molecular Biology Techniques
                Genetic Fingerprinting and Footprinting
                Genetic Footprinting
                Biology and Life Sciences
                Genetics
                Gene Expression
                Protein Translation
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Drosophila Melanogaster
                Biology and Life Sciences
                Organisms
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Peroxisomes
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Mammals

                Genetics
                Genetics

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