Title:U1 snRNP Control of 3´-End Processing and the Therapeutic Application of U1 Inhibition Combined with RNA Interference
VOLUME: 13 ISSUE: 7
Author(s):L. Blazquez and P. Fortes
Affiliation:Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA). University of Navarra, Pio XII 55. 31008 Pamplona. Spain.
Keywords:Gene expression inhibition, polyadenylation, premature cleavage and polyadenylation, RNA
interference (RNAi), U1-70K, U1 adaptors, U1 interference (U1i), U1 snRNA.
Abstract:U1 snRNP (U1 small nuclear ribonucleoprotein) is a well-characterized splicing factor. Besides,
when U1 snRNP binds close to a putative polyadenylation site, mostly located in introns, it prevents premature
cleavage and polyadenylation and controls the length of most cellular mRNAs. On the other hand, U1 snRNP
binding close to the 3´-end of some mRNAs, inhibits polyadenylation and, therefore, gene expression. The
inhibition of polyadenylation by U1 snRNP is the basis of U1i (U1 snRNP-based inhibition), a technique used to
inhibit gene expression. U1i consists of the expression of a U1 snRNP modified to interact with a target mRNA
and inhibit target gene expression. U1i has been used to inhibit the expression of reporter or endogenous
genes both in tissue culture and in animal models. Furthermore, combination of U1i and RNA interference
(RNAi) results in synergistic increased inhibitions which allow the dose of inhibitors to be decreased whilst at
the same time obtaining good inhibitions with fewer unwanted secondary effects. The combination of RNAi and
U1i is of special interest for antiviral therapy, as a functional decrease of the expression of replicative viral
RNAs may require high inhibition and the combination of two or more inhibitors should decrease the possibility
of escape mutants resistant to treatment. In fact, a therapy with U1i combined with RNAi is currently being
developed for the treatment of HBV infections. We believe that this review will clarify the hallmarks of U1i
technology and will encourage many laboratories to use U1i for functional studies and therapeutic applications.
