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Review
. 2009;5(2):97-117.
doi: 10.7150/ijbs.5.97. Epub 2009 Jan 15.

The fascinating world of RNA interference

Afsar Raza Naqvi  1 , Md Nazrul Islam, Nirupam Roy Choudhury, Qazi Mohd Rizwanul Haq
Affiliations
Review

The fascinating world of RNA interference

Afsar Raza Naqvi et al. Int J Biol Sci. 2009.

Abstract

Micro- and short-interfering RNAs represent small RNA family that are recognized as critical regulatory species across the eukaryotes. Recent high-throughput sequencing have revealed two more hidden players of the cellular small RNA pool. Reported in mammals and Caenorhabditis elegans respectively, these new small RNAs are named piwi-interacting RNAs (piRNAs) and 21U-RNAs. Moreover, small RNAs including miRNAs have been identified in unicellular alga Chlamydomonas reinhardtii, redefining the earlier concept of multi-cellularity restricted presence of these molecules. The discovery of these species of small RNAs has allowed us to understand better the usage of genome and the number of genes present but also have complicated the situation in terms of biochemical attributes and functional genesis of these molecules. Nonetheless, these new pools of knowledge have opened up avenues for unraveling the finer details of the small RNA mediated pathways.

Keywords: 21-U RNA; argonaute; dicer; miRNA; mirtron.; piRNA; siRNA.

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Conflict of interest statement

Conflict of Interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
siRNA pathway: Precursor dsRNA are generated by either (a) RNA dependent RNA polymerase (RdRP) activity on aberrant transcripts or (b) transcript having full or partial complementarity. (c) These are recognized and processed by nuclear Dicer (different from the one involved in microRNA pathway) and this siRNA-Dicer complex is then exported to cytoplasm. (d) The siRNA- Dicer complex then recruits Argonaute that unwind the duplex to form si-RISC/RITS. (e) Transcripts bearing complementary sequences to guide siRNA strand are cleaved by RNase activity of Argonaute2. (f) To confer immunity, siRNAs-Dicer complex may also traffic in systemic fashion (g) that is achieved by Systemic RNA Interference-Defective (SID-1; in animals)/ Phloem Small RNA binding protein-1 (PSRP1; in plants). (h) The exogenous siRNA pathway follows parallel to endogenous pathway, but differs in the fact that the cytoplasmic Dicer generates the siRNA duplexes. The RITS complex lead to transcriptional gene silencing that involves various proteins.
Figure 2
Figure 2
The general domain organization of (a) Dicer and (b) Argonaute proteins. The functions of few domains that have been predicted through crystal structures and mutant analysis are mentioned.
Figure 3
Figure 3
MicroRNA pathway: (a) After being transcribed, the pri-miRNAs stem-loop structure is acted upon by (b) Drosha (that also confers to miRNA strand and target specificity) and generates pre-miRNA. Sometimes, these precursors are edited by Adenosine Deaminase Acting on RNA (ADARs) at specific positions (generally +4 and +44) changing adenine to inosine. In plants, the DCL1 generates miR duplex in the nucleus that is methylated at terminal bases by HEN1. (c) These are then transported to cytoplasm with the assistance of Exportin-5/ HASTY. From here (d) Dicer comes into play (in animals) and generates miRNA duplexes that will be incorporated into micro Ribo-Nucleo-Protein (mi-RNP) complex. After the removal of passenger strand mature miRNA then guides the functional protein complex to the targets. (e) In mammals, miRNAs bearing nuclear signal sequences can traffic back to the nucleus. Depending upon the proteins associated with miRNA leads to either (f) cleavage of target mRNA or modulate the translation turnover by (g) translation activation or repression of respective mRNAs. The repressed mRNAs are transferred to structures called P-bodies.
Figure 4
Figure 4
Schematic diagram to depict differences between mirtron and canonical miRNA generation. Introns that assume foldback structures are recognized and cleaved by DROSHA. These stem-loop lariats are then acted upon by Lariat debranching enzyme that cleaves the phosphor-diester bond formed during splicing event. The pri- miR thus formed joins the mainstream miRNA flux, before making exit to cytoplasm.
Figure 5
Figure 5
Schematic representation of the pri-miRNA transcripts of (i) animal, (ii) plant, and (iii) alga showing differences in the miRNA biogenesis. Note that not all animal and algal pri-miRNAs follow this structural representation but it holds for plants where single miRNA resides within pri-miRNA stem.
Figure 6
Figure 6
Schematic representation of time-point specific expression each piRNA species follows during spermatogenesis.
Figure 7
Figure 7
piRNA biogenesis pathway. (a) Usually a polycistronic transcript, driven by mono- or bidirectional promoter, generates piRNAs by an unknown mechanism. Since the precursor lacks any tendency to achieve double-stranded form, the piRNA biogenesis seemed to be different from other small RNAs. (b) The biogenesis requires template to catalyze generation of desired small RNAs which further cleave corresponding target messages with another set of proteins. These piRNA may either regulate genome organization by checking transposon mobility or move to cytoplasm to take care of cognate messages either by cleaving or stabilizing them.
Figure 8
Figure 8
General structure of 21U-RNA locus
Figure 9
Figure 9
21U-RNA pathway. Dictated by their own promoters, the independent transcripts are made that may involve specific factors to sense the terminal U residue and the 21 nt, thereby releasing mature 21-U RNAs.
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