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RNA Interference: an Evolutionary Pathway in Periodontal Tissue Engineering

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RNA Interference: an Evolutionary Pathway in Periodontal Tissue Engineering REVIEW ARTICLE RNA Interference: An ISSN No 2230-7885 CODEN JPBSCT Evolutionary Pathway NLM Title J Pharm Biomed Sci in Periodontal Tissue Swyeta Jain Gupta1,*, Amit Gupta2, Engineering Vivek Gautam3, Kaushik Kumar Pandey4, ABSTRACT Swati Choudhary5 RNA interference (RNAi) is an evolutionary conserved silencing pathway in which the 1 double-stranded RNA is broken down into small interfering RNA (siRNA) with the help of Senior Lecturer, Department of dicer and RNA-induced silencing complex (RISC) complex by a series of steps. Pioneering Periodontics and Implantology, I.T.S. observations on RNAi were reported in plants, but later on RNAi-related events were Centre for Dental Studies and Research, described in almost all eukaryotic organisms, including protozoa, flies, nematodes, Ghaziabad, Uttar Pradesh, India insects, parasites, and mouse and human cell lines. 2 Senior Lecturer, Department of Oral and Maxillofacial Pathology and Microbiology, KEYWORDS gene silencing, RNAi, DICER, RISC I.T.S. Dental College, Hospital and Research Centre, Greater Noida, Uttar Pradesh, India INTRODUCTION 3 Prosthodontics (Private practitioner), Gautam Multispeciality Dental Clinic, The RNA-mediated silencing process is defined as RNAi, a discovery for P N Plaza Complex, Sigra, Varanasi, which Fire and Mellow received the 2006 Nobel Prize1. RNA interference Uttar Pradesh, India (RNAi) is a phenomenon primarily described as interference by RNA in the 4 Department of Prosthodontics Career expression of genetic information. It is a phenomenon primarily for the reg- Postgraduate Institute of Dental Science ulation of gene expression; self or non self depending upon the surrounding and Hospital, Lucknow, Uttar Pradesh, India factors or conditions, with the help of RNA molecules that are non coding 5 Oral and Maxilllofacial Pathology, in nature to control cellular metabolism and help in maintaining genomic Delhi, India 2 integrity by preventing the invasion of viruses and mobile genetic elements . Address reprint requests to The discovery of RNAi has opened the door to RNA-based therapeutics that *Dr. Swyeta Jain Gupta, Senior Lecturer, may prove to be an effective tool for the treatment of a large variety of dis- Department of Periodontics and Implantology, eases and for tissue regeneration, including periodontal tissue regeneration3. I.T.S. Centre for Dental Studies and RNA silencing a novel gene regulatory mechanism limits the transcript level Research, Ghaziabad, Uttar Pradesh, India E-mail: [email protected] by either suppressing transcription (transcriptional gene silencing [TGS]) or by activating a sequence-specific RNA degradation process (posttran- Article citation: Gupta SJ, Gupta A, scriptional gene silencing [PTGS]/RNA interference [RNAi]). RNAi works Gautam V, Pandey KK, Choudhary S. RNA interference: an evolutionary pathway in through small RNAs of approximately 20 to 30 nucleotides. Although there periodontal tissue engineering. J Pharm is a mechanistic connection between TGS and PTGS, TGS is an emerging Biomed Sci 2016;06(01):39–43. 4,5 field while PTGS is undergoing an explosion in its information content . Available at www.jpbms.info RNA interference and its focus on the experimental results related to tissue 6 Statement of originality of work: The engineering have led to conceptual advancements in this field . manuscript has been read and approved by all the authors, the requirements for authorship have been met, and that each author believes that the HISTORY manuscript represents honest and original work. RNA molecules were earlier believed to serve only as messengers, bearing Source of funding: None. genetic information from DNA. But in the early 1980s it was revealed in Competing interest / Conflict of interest: The Escherichia coli that small RNA molecules (about 100 nucleotides in length) author(s) have no competing interests for financial can bind to a complementary sequence in mRNA and inhibit transla- support, publication of this research, patents, tion7. This inactivates mRNA and therefore prevents it from passing on and royalties through this collaborative research. the genetic information. The phenomena of RNAi first came into notice All authors were equally involved in discussed in the year 1990, when plant scientists were trying to intensify the hue research work. There is no financial conflict with the subject matter discussed in the manuscript. of red petunias for commercial benefits. Rich Jorgensen introduced a gene that controls the formation of red pigments in petunia flowers but Disclaimer: Any views expressed in this in some cases it was observed that the colour disappeared altogether. The paper are those of the authors and do not reflect the official policy or position of the phenomenon was named as co-suppression. Co-suppression is a classical Department of Defense. form of eukaryotic post-transcriptional gene silencing. The reason behind such an observation was not clear at that time until it was reported in Copyright © 2016 Received Date: 12 December 2015 – Accepted Date: 19 December 2015 – Published Online: 16 January 2016 40 Swyeta Jain Gupta transgenic petunia, where a sense transgene meant to RNA (siRNA) and the organism-specific systemic trans- overexpress the host Chalcone Synthase-A (CHS-A) gene mission of silencing from its site of initiation. caused the degradation of the homologous transcripts and the loss of flower pigmentation. Subsequently such MECHANISM OF RNA INTERFERENCE phenomenon was also observed in fungi, which was termed as quelling7,8. In animals, RNA silencing was Mechanism of RNA interferences as understood is first reported when Guo and Kemphues9 were attempt- that it comes into play when a double stranded RNA ing to use antisense RNA to shut down expression of is introduced either naturally or artificially in a cell. the par-1 gene in order to assess its function. More An endoribonuclease enzyme cleaves the long dsRNA recently, micro-RNA formation, heterochromatiniza- into small pieces of RNA. The small pieces could be tion, etc., have been revealed as other facets of natu- miRNA or siRNA depending upon the origin of long rally occurring RNAi processes of eukaryotic cells. As dsRNA i.e. endogenous or exogenous, respectively. A expected, injection of the antisense RNA disrupted double-stranded RNA may be generated by either RNA expression of par-1, but quizzically, injection of the dependent RNA polymerase or bidirectional transcrip- sense-strand control did too used antisense RNA to tion of transposable elements or physically introduced. block par-1 mRNA expression in Caenorhabditis elegans but The mechanism of RNA interference can be divided found that the par-1 mRNA itself also repressed par-1. into two stages: (1) initiation and (2) effector. Their paradoxical observation—subsequently dubbed RNA interference (RNAi)—inspired the experiments Initiation of Fire, Mellow, and colleagues10,11. Fire et al.12 studied on the gene function especially This stage is characterised by the generation of siRNA on the gene responsible for movement in C. elegans. When mediated by type III endonuclease Dicer. In Drosophila, this nematods were injected with the mixture of sense Dicer, which is a large multidomain RNase III enzyme and antisense RNA, nematodes were observed with the has been identified in existence into two forms: Dcr-1/ impaired movement suggesting a defective muscle gene Loquacious (Loqs)-PB (also known as R3D1-L[long]): protein. They concluded that the dsRNA injected must generate miRNA and Dcr-2/R2D2 generates siRNA14,15. match the mature “trimmed” mRNA sequence for the Dcr-1 share a structural homology with Dcr-2, despite gene and the interference could not be elicited by intron that they display different sets of properties such as sequences. This implies that interference takes place after ATP requirements and substrate specifications. Dcr-1 is transcription, probably in the cytoplasm rather than in an enzyme that shows ATP independent functions and the cell nucleus12. affinity towards stem-loop form of RNA (precursor of During the occurrence of RNAi/PTGS, the mRNA miRNA). It has been identified that Dcr-1 requires a was revealed to be targeted with large complex double-stranded RNA binding protein partner14,16. In proteins to form RNA induced silencing complex, Drosophila Dicer-1 is seen to interact with the dsRBD commonly called RISC; in association with si RNA. protein Loquacious (Loqs). Immunoaffinity purifica- Subsequently, it has been shown that RISC contains tion experiments reveal that Loqs resides in a functional at least one member of the argonaute protein family, pre-miRNA processing complex, and stimulates and which is likely to act as an endonuclease and cut the directs specific pre-miRNA processing activity. These mRNA (often referred to as the Slicer function). It results support a model in which Loqs mediates miRNA was also demonstrated that a ribonuclease like nucle- biogenesis and, thereby, the expression of genes regu- ase, called Dicer, is responsible for the processing of lated by miRNAs. Loquacious protein is supposed to be dsRNA to short RNA. In certain systems, in particu- composed of three dsRNA binding domains, which is lar plants, worms and fungi, an RNA dependent RNA encoded by loqs gene into two types of proteins PA and polymerase (RdRP) plays an important role in gener- PB; isoform to each other, by alternate splicing, among ating and/or amplifying siRNA13. which PB is known to enhance the affinity of Dcr-1 towards pre-miRNA. Dcr-2 shows ATP dependent activ- IMPORTANT FEATURES OF RNA SILENCING ity with substrate specificity to double stranded RNA. Structurally homologous to Dcr-1, also requires a The critical common components of the paradigm double-stranded RNA binding protein, namely R2D2, are that which function in association with specific RNase enzyme Dcr-2 forming a heterodimeric complex. i. the inducer is the dsRNA, R2D2, unlike Loq is supposed to be composed of two ii. the target RNA is degraded in a homology dsRNA binding domains that interact with long double dependent fashion, and the degradative machinery stranded RNA but does not regulate siRNA generating requires a set of proteins which are similar in activity of Dcr-2.
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