Micro RNA / SiRNA
Phillip D. Zamore, University of Massachusetts Medical School
MicroRNAs (miRNAs), small interfering RNAs (siRNAs), and repeat-associated small interfering RNAs (rasiRNAs) are 21- to 30-nucleotide long guides that direct protein complexes to regulate the expression of specific sets of genes, generally by turning off mRNA production, increasing the rate of mRNA destruction, or blocking translation of mRNA into protein. Collectively, the pathways in which small RNAs act are called RNA silencing. The best studied RNA silencing pathway is the RNA interference (RNAi) pathway, in which long, exogenous double-stranded RNA (dsRNA) triggers the destruction of mRNAs sharing sequence with the dsRNA. In flies and humans small RNAs are produced by members of the RNase III family of dsRNA-specific endonucleases, with each endonuclease collaborating with a dsRNA-binding partner protein. The resulting small RNAs are double-stranded, and the two strands must be parted before they can function to silence genes. At least three different mechanisms act to separate the small RNA strands and load one strand into RNA silencing effector complexes. Each of these loading complexes may contain a distinct set of double-stranded RNA-binding proteins. Fifteen years after the discovery of RNA silencing, we are only just beginning to understand the depth and complexity of how small RNAs regulate gene expression and to consider their role in shaping the evolutionary history of higher eukaryotes. Despite the rapid progress we have made in the last five years, our answers to the central questions of RNA silencing remain incomplete. What enzymes produce small RNAs and how do these enzymes recognize authentic silencing triggers? How are small RNAs loaded into the protein-RNA complexes that regulate genes and what purpose does the diversity of loading and effector complexes serve? What cellular processes are regulated by RNA silencing pathways and why?