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Genes Appear Very Much to Be Blueprints for Primary Mrna

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Genes Appear Very Much to Be Blueprints for Primary Mrna FEATURE ARTICLE Genes and Protein Synthesis— Updating Our Understanding • TIMOTHY P. BRADY ABSTRACT possibility that these phenomena, properly considered, suggest the That genes are indispensable is indisputable but that they are the source of need to qualify the paradigm that insists genes largely dictate to cells information for protein synthesis—to the extent reflected by statements such as and organisms via genetic influence on protein synthesis. “genes are blueprints for proteins” or “genomes constitute developmental programs”—is challenged by discoveries such as post-translational modification of protein and alternative splicing. Post-Translational Modification of Protein Key Words: alternative splicing; post-translational modification of protein; mRNA editing; primary mRNA transcript; functional (mature) mRNA transcript; alternative PTM provides for the covalent attachment of chemical groups such transcript; protein isoforms. as phosphate or the acetyl group or sugar moieties, or even larger groups such as ubiquitin, to amino acid residues of proteins. Most eukaryotic proteins are post-translationally modified after their syn- thesis on ribosomes and these modifications are critical for the pro- Introduction tein’s functioning and for getting the protein to the site in the cell where it needs to be to in order to carry out its function (Reece I take it for granted that genetics teaching, at both the high school et al., 2014, pp. 351–352). In the next section, examples of PTM and undergraduate levels, pretty much reinforces the longstanding are provided to show the extent to which modification status can belief that genes are, ultimately, blueprints for influence protein function and to show the proteins and, given the workhorse nature of extent to which factors other than the nucleo- proteins, that organisms’ genomes constitute Genes appear very tide sequence of the associated gene can influ- the blueprints for making organisms. The ence modification status. Any influence by a Next-Generation Science Standards’ Disciplin- much to be blueprints factor that is not itself a direct product of a ary Core Ideas include L.S.1.A., “Genes are for primary mRNA gene is termed “non-genetic.” regions in the DNA that contain the instruc- tions that code for the formation of proteins. .” molecules but not Evidence for Context-Dependence and L.S.3.A., “The instructions for forming of PTM, Including Non-Genetic species’ characteristics are carried in DNA” blueprints for the Context Dependence (NGSS, n.d.). The premise of this paper, how- functional mRNA PTM appears to be a very dynamic process. For ever, is that consideration of the influence instance, all of the examples of PTM men- post-translational modification of protein molecules resulting tioned above are reversible (Prabakaran et al., (PTM) and alternative splicing (AS) have on 2012, HHS Public Access Version, p. 28). protein synthesis and consideration of the fac- from AS. These authors also stress the combinatorial tors involved in regulating these processes cast possibilities associated with PTM as suggesting doubt on the continued appropriateness of the gene-as-blueprint its dynamic nature and provide the following example to make clear and genome-as-developmental-program metaphors. AP biology their understanding of “combinatorial.” If a particular lysine residue textbooks do discuss PTM and AS, over-looking, though, the can bind an ubiquitin, and a second ubiquitin can bind to the first, The American Biology Teacher, Vol. 80, No. 9, pp. 642–648, ISSN 0002-7685, electronic ISSN 1938-4211. © 2018 National Association of Biology Teachers. All rights reserved. Please direct all requests for permission to photocopy or reproduce article content through the University of California Press’s Reprints and Permissions web page, www.ucpress.edu/journals.php?p=reprints. DOI: https://doi.org/10.1525/abt.2018.80.9.642. 642 THE AMERICAN BIOLOGY TEACHER VOLUME 80, NO. 9, NOVEMBER/DECEMBER 2018 and this same protein has two serine residues, each of which can GC’s influence on phosphorylation here to be non-genetic. Steroid bind a phosphate group, then this one protein can exist in 12 differ- hormones are not direct products of genes, and even though gene- ent “mod-forms” (p. 24). A mod-form according to these authors is associated proteins are needed for GC synthesis, GCs can, in nega- “a specific pattern of modifications on all modifiable residues in a tive-feedback fashion, down-regulate plasma levels of two of them, protein” (p. 4). In Mohapatra et al. (2007; cited by Prabakaran et corticotrophin-releasing factor (CRH) and adrenocorticotropic hor- al., 2012), non-genetic and combinatorial control of a protein’s func- mone (ACTH) (Oakley & Cidlowski, 2013, p. 1033). Additionally, tionality is illustrated along with a certain context-dependence. Evi- bloodstream GC levels vary in circadian fashion (Chung et al., dence is presented that an increase in neuronal electrical activity 2011b), this suggesting a role for day/night cycling in the regulation triggers protein de-phosphorylation and that a cell-type specific cor- of GC synthesis. Finally, different types of stress trigger CRH and relation exists between extent of phosphorylation and membrane concomitant GC synthesis (Chung et al., 2011b, p. 583). potential needed for protein activation (pp. 1064–1065). That this The cytoplasmic moiety of a B2 adrenergic receptor must be protein’s functioning changes according to degree of phosphoryla- phosphorylated for receptor coupling to occur, and prior palmitoy- tion, which depends on cell type, suggests that cell-specific factors lation of the cytoplasmic moiety is required for phosphorylation and not just the nucleotide sequence of the associated gene influence (Chini & Parenti, 2009, p. 374). Although the information stored the phosphorylation status and, hence, the function of this protein. in the receptor’s biocynthetic gene is necessary for synthesis of this Tootle and Rebay (2005) provide several examples of the impor- protein, it would seem apparent that knowledge of when to attach a tance of context-dependent PTM for transcription-factor function- palmitic acid to the receptor, and when not to, would have to reside ing. In one example, phosphorylation activates a transcription elsewhere than in that gene. factor, this promoting transcription of a gene whose protein product is involved in lymphoid tissue differentiation; when a second type of Implications of PTM for Conceptualizing the Role of kinase phosphorylates the same transcription factor, curtailment of Genes in Protein Synthesis activity occurs (pp. 290–291). Acetylation of this transcription factor A serine residue on protein A can be phosphorylated while that causes it to play a role in the regulation of extra-cellular-matrix pro- same residue on another molecule of A can be glycosylated teins (p. 291). These authors also discuss a transcription factor local- (Prabakaran et al., 2012, p. 4). Light-engendered photosynthesis ized to the cytoplasm of T lymphocytes until the cell’s differentiation triggers an enzyme’s dephosphorylation. A transcription factor’s status changes; then, the transcription factor is both phosphorylated function changes depending on which kinase phosphorylates it and glycosylated and, as a result, moves into the nucleus (p. 294). and changes again if it’s acetylated. The extent of neuronal electrical Phosphorylation can only occur here if the transcription factor con- activity dictates the phosphorylation status of a channel protein tains an amino acid residue with a hydroxyl group capable of bind- associated with that neuron. Of course, there would be no proteins ing a phosphate. For this, the transcription factor’s biosynthetic gene to modify without genes. Still, the reversible nature of PTM, its con- plays a necessary role, as does the phosphorylating kinase and its text-dependence, and its combinatorial aspect, suggest PTM occurs biosynthetic gene. However, these are not sufficient to explain this according to the dictates of a regulatory web whose information phosphorylation event because this transcription factor is not always store must greatly exceed that of the associated gene. Indeed, it phosphorylated—it’s only phosphorylated when there’s a require- would not have been possible to predict any of the protein modifi- ment that it move into the nucleus. cations discussed above solely from the nucleotide sequence of the Brassinosteroids (BRs), plant steroid hormones, trigger phos- relevant gene. This is not contradicted by the fact that software phorylation of an enzyme, leading to activation of a transcription exists (Chen et al., 2016) that can infer from the nucleotide factor that turns on expression of BR-sensitive genes (Hill, 2015, sequence of a region of a gene and that region’s modification status pp. 4934–4935). I consider the BR influence here to be non-genetic what the likelihood will be of that same modification occurring in because BRs, and steroid hormones in general, are not direct prod- other proteins. Software such as this can only predict the likelihood ucts of genes, and even though BRs do require gene-associated that a particular modification can occur, not that it will occur. To enzymes for their synthesis, BRs help regulate transcription of these achieve the latter, for modifications that are context-dependent, rel- genes (Vriet et al., 2013, p. 1749). Also, auxin, another hormone, evant context would have to be taken into consideration. triggers a rate-determining step
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