Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Abstract

The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the "Central Dogma of Molecular Biology", has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNAdependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesis found to occur in mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained in several systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundance of a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer's disease. The increased understanding of components and mechanisms involved in RNA-dependent mammalian mRNA amplification could open up new approaches not only for therapeutic interference in multiple pathologies but also for novel and powerful forms of bioengineering. The aim of the present article is to systematize the current knowledge and understanding of this pathway. The outlined framework introduces unexpected features of the mRNA amplification such as its second Tier, a physiologically occurring intracellular PCR, iPCR, a "Two-Tier Paradox" and RNA "Dark Matter". It also describes novel experimental bioengineering designs and may serve as a basis for new directions of investigations into the mechanisms underlying the mammalian mRNA amplification processes.