title: Coupling of transcription termination to RNAi.
abstract: In metazoans, the mechanisms of transcriptional termination by RNA polymerase II (Pol II) and accelerated decay of messenger RNA (mRNA) following transcription shutdown are linked by sharing the same sequence elements and mRNA elongation, processing and termination factors. This begs the question, how could one process have two opposite outcomes, making or degrading mRNA? An integrated "allosteric-GENEi-torpedo" model that could explain this paradox predicts participation of two novel factors: (1) An allosteric factor, regulated by a physiological repressor, binds to a unique sequence element of a gene near the site of cleavage and polyadenylation, poly(A) site, and acts on the homologous site on the nascent transcript to cause its cleavage. The conformational changes of this factor determine the fate of nascent RNA, either to get cleaved and processed to mature mRNA for directing protein synthesis, or not to get cleaved and become template for double-stranded (ds) RNA synthesis. (2) A general transcription termination factor, recruited by transcribing Pol II at the poly(A) site, allostrically alters and induces Pol II to switch template from DNA to nascent RNA several hundred nucleotides downstream of the poly(A) site. The template switch disengages Pol II from DNA and effectively terminates transcription. The Pol II with newly acquired RNA-dependent RNA polymerase activity retraces its path, back along the nascent RNA, so generating dsRNA. The extent to which it can retrace this path is determined by the factors influencing the cleavage of the pre-mRNA at the site of polyA addition. If cleavage and polyadenylation occur, the retracing is cut short, the 3' RNA is degraded by an exonuclease and the polymerase is liberated to reinitiate transcription. If the cleavage is inhibited, then a full-length dsRNA can be produced. This can then be subject to cleavage by "Dicer", which generates fragments of approximately 22bp that guide degradation of the cognate mRNA via the RNA interference (RNAi) pathway. This model complements the current "allosteric-torpedo" model of transcription termination, and could explain the apparent paradox of the divergent results of a common biological process.
authors.affiliation: Impedagen, LLC, 175 Brushy Plain Road, Suite 3-C6, Branford, CT 06405-2617, USA. bbahramian@impedagen.com <bbahramian@impedagen.com>
authors.forename: M
authors.initials: M
authors.lastname: Bahman Bahramian
mesh_terms: D053487:DEAD-box RNA Helicases / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics; D008957:Models, Genetic; D034622:RNA Interference; D012319:RNA Polymerase II / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D043244:Ribonuclease III; D013728:Terminator Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D012319:RNA Polymerase II; D004722:Endoribonucleases; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases