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  1. Why "Koonin's epigenetic inheritance of prion encrypts might be too 'super-stream''

    Misaki Wayengera, College of Health Sciences, Makerere University

    26 January 2015

    I would like to congratulate Koonin EV [1] and indeed this journal, on this-- is predictable to be a fundamental paradigm shifting, publication.

    The matters articulated here are over half a decade old, and-I am sorry to say, it makes me sympathize with Griffith JS [2]'s earlier efforts to put forth a `model for self replication of prion¿ based on a reversal of the Central Dogma. Indeed, I am suspicious that Koonin was in this case only able to by pass ¿reviewers¿ potential inertia against the idea of a reversed Central dogma¿ by riding the embers of epigenetics.

    I say so, because, in the past-we (hoping that the timing of Thomas Khun¿s paradigm shift -for the Central Dogma was ready) have unsuccessfully attempted the rather direct stunts, and miserably failed. See, a direct attack on the `central dogma¿, though 'partially' archived by Temin and Baltimore [3, 4] in the 70s when the brought to light the acitivity of the retroviral RNA dependent DNA polymerase (RdDp), seems too radical and up-stream to provide supportive evidence for in its entirety. Specifically, in order to propose a fully `reverse translated, reverse transcribed¿ for the intracellular replication of prions (you may say proteins now), ones needs a number of things¿all of whose evidence is absent today. Specifically, in the context of prion-proteins (PrP); you require evidence for:

    (i) prion protein (PrP) coding genes and their respective RNA. Whereas this evidence exists for cellular prions (PrPC), no such evidence exists for the pathogenic ¿scrapie¿ prions (PrPC).
    (ii) Reverse translase (abbreviated, RTLase) activity
    (iii) Sustainable accommodation-ability of ¿degeneracy in the genetic code¿ in the species

    The prevailing picture presented us by the protein only hypothesis¿that the disease causing prion-proteins (PrPSc) replicate in-vivo by inducing misfolded states or changes within the conformation of the normal cellular prion proteins (PrPC) nevertheless remains rather `vague in the context of a fully reverse central dogma¿, and is only accommodated-able, as Koonin has successfully achieved here, within the far down-stream, indeed super-stream, of epigenetics. Two models_heterodimer and fibril, have been proposed to explain how PrPSc forces PrPC into misfolds that yield more PrPSc. In the heterodimer model, it is thought that a second unidentified protein X binds to PrPC, with the issuing PrPC/ protein X complex binding PrPSc to yield (by a still unknown process) the second PrPSc. That¿s why, amidst the many existing un-relatedness, we previously unsuccessfully (since the two papers were never accepted for press) attempted to propose a different model for the intracellular replication of prions in which the PrPC/Protein X complex may act as a reverse-translase.

    We observed that¿ although it was previously proposed that prions may self-replicate by Griffith[2], this was contested by Crick[1] on the argument that the flow of sequence information from protein to protein, or from protein to RNA and DNA is "precluded". Neverthless, following the discovery of reverse transcription in retroviruses [3,4], a revised hypothesis to accommodate the RNA dependant DNA polymerase (RdDp) enzyme reverse transcriptase was acknowledged.

    On basis of the above, we revisited self replication of prions by proposing a dual ¿reverse-forward¿ model comprising of (i) an early PrPSc gene un-masking stage wherein a reversal of the two steps in the central dogma of molecular biology (reverse-translation of PrPSc to its PrPSc encoded +ve ss mRNA, followed by reverse-transcription of the PrPSc encoded mRNA to dsDNA) occurs to yield the PrPSc coding gene, and (ii) a late PrPSc gene-expression stage employing the conventional forwards central dogma of molecular genetics to yield new PrPSc.

    Such a model predicts the existence of protein dependant RNA polymerase (PdRp or reverse-translase, RTLase) activity. PdRp activity can hypothetically either only-functionally be achieved in the susceptible host through PrPC/ protein X complexion, or it is natively structurally present within the prion. Overall, probes for the hypothetical PrPSc DNA/RNA would be usable as novel diagnostics for TSE, while inhibitors of those specific enzymes involved at the various stages in the prion ¿reverse-forward¿ dogma could possess anti-prion therapeutic (APT) activity.

    While It is difficult to search for a new protein activity such as PdRp from within the existing databases, since you have no reference homologue, we postulated that any integral prion PdRp should manifest both Protein dependant RNA polymerse (PdRP) as well as RNA dependant DNA polymerase (RdDp, or reverse transcriptase). That¿s why, the human PrPC protein sequences (UniprotKB/TrEMBLE accession # tr|Q540C4|Q540C4) were blasted against the NBCI retroviral resource; yielding hits of 25-56% identity to Avian Leukosis virus (AVL) env-polyprotein, Simian immunodeficiency virus (SIV) nef, and Feline foamy virus (FFV) gag. A similar blast of human PrPC protein sequences across the HIV sequence database yielded relatively higher and functionally undisputable similarity (37- 63% identity) of PrPC to HIV-1 and 2 envelope, LTR, gag, and pol (intergrase) sequences. Multiple sequence alignments and conserved motif searches revealed a conservation of cAMP- and cGMP-dependent protein kinase phosphorylation, Prenyl group binding, N-glycosylation and myristoylation, and Casein kinase II phosphorylation sites. Second, the 3D structure of the human PrPC protein was compared to the more characterized HIV-1 envelope, nef, gag, and RTase proteins¿with findings of minor (21- 35%) yet-still proteomically undisputable functional similarities between human PrPC protein and HIV-1 nef and RTase but not the p24 capsid of gag.

    Whether or not, the above findings should convince the field to re-consider Griffith¿s prior concepts, is a subject of debate and one that is hereby only tactically yet scientifically successfully overcome by Koonin. Overall, more of the much needed non-specific support for the ¿fully reversed, fully-forwarded¿ dogma of the molecular genetics of prions, can be adduced from the following arguments.

    (a) Firstly, several retroviruses¿by operating reverse transcriptase or RdDp enzymatic activity, can integrate their genomes into the host genomes. As a consequence, there are several residual elements of retro-proviral DNA passage within host genomes. These are the long interspersed nuclear elements (LINEs) of long terminal repeats (LTR) nature denoted, in man- as the human endogenous retro-elements (HEREs) [5, 6]. Elsewhere, this evidence may be adduced by retroposons, transposable elements of group II intron(s) classification. The presence of the PrPC gene-PRNP, within the human and possibly other mammalian genomes may thus be argued to be the prion-archeological evidence for a related phenomenon (that is, evidence for the historical integration of transient PrPSc genes in the host genome following inter-species transmission events).

    (b) Secondly, if prions possess within them the enzymatic machinery required to initiate the ¿fully reversed, fully-forwarded¿ dogma, the same would circumstantially serve to rejuvenate the earlier self- replication model of prions proposed by Griffith JS [2], as well as expand the debate on what biological macromolecules were the first to appear after the big-bang, and thereby are the source of life from just RNA and DNA to that inclusive of proteins-alone. Specifically, if prions are found to have PdRp/RdDp activity, this may support the theories of spontaneous abiogenesis or biopoesis (that describe how life arose from inorganic matter through natural processes or the method by which life on Earth first emerged). While most amino acids, often called `the building blocks of life¿, have prior been spontaneously generated by natural chemical reactions unrelated to life, as demonstrated in the Miller¿Urey [7] experiment and similar experiments that involved simulating some of the hypothetical conditions of the early Earth in a laboratory, the presence of a PdRp/RdDp activity would make the entire occurrence a more downstream and feasible spontaneous in-vivo process. In all living things, at least before this, it has been `wrongly¿ assumed that these amino acids are organized into proteins, and the construction of these proteins is mediated by information encoded within nucleic acids. The `fully reversed, fully forwarded¿ dogma however offers us the basis to historically or evolutionarily argue the reverse-- that the nature and code within the current nucleic acids was originally, or can prospectively be encoded by proteins. This makes a very strong case for proteins (amino acids) as the first macromolecules that formed the first life, the theme of abiogenesis [8].

    (c ) Thirdly, the `fully reversed, fully forwarded¿ dogma accounts for the variations in the strains of prions, which is not explained by the existing protein-only models [9, 10]. Specifically, because of the degeneracy of the genetic code_only 24 amino acids for the universal 64 codons (triplets of bases coding an each amino acid), more than one option of codons can emerge from each single amino acid(s) constituting the prion protein PrPSc.

    Who knows, perhaps this more agreeable epigenetic-link now offered us by Koonin [1] will eventually revive the quest into the unpopular mists surrounding the physical activity of PdRp and a fully reversed- central dogma, in direct antagonism to Crick's prior `thoughts¿.


    1. Koonin EV: Does the central dogma still stand? Biology Direct 2012, 7:27
    2. Griffith JS: Self-replication and scrapie. Nature 1967, 215 (5105): 1043¿1044.
    3. Temin HM, Mizutani S: Viral RNA-dependent DNA Polymerase: RNA-dependent DNA Polymerase in Virions of Rous Sarcoma Virus. Nature 1970, 226 (5252): 1211¿1213.
    4. Baltimore D: Viral RNA-dependent DNA Polymerase: RNA-dependent DNA Polymerase in Virions of RNA Tumour Viruses. Nature 1970, 226 (5252): 1209¿1211.
    5. Zupunski V, Gubensek F, Kordis D: Evolutionary dynamics and evolutionary hiistory in the RTE clade of non-LTR retrotransposons. Mol Biol Evol 2001, 8(10):1849-1863.
    6. International Human Genome Sequencing Consortium: Finishing the euchromatic sequence of the human genome. Nature 2004, 431:931-945.
    7. Miller SL, Urey HC: Organic Compound Synthesis on the Primitive Earth.Science 1959, 130 (3370): 245.
    8. Hill HG, Nuth JA: The catalytic potential of cosmic dust: implications for prebiotic chemistry in the solar nebula and other protoplanetary systems. Astrobiology 2003, 3 (2): 291¿304.
    9. Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB: Structural clues to prion replication. Science 1994, 265 (5178): 530¿531
    10. Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE: Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations. Cold Spring Harbor Symposium on Quantitative Biology 1996, 61: 495¿509.

    Competing interests