RRC ID 45904
Author Zhou X, Xu F, Mao H, Ji J, Yin M, Feng X, Guang S.
Title Nuclear RNAi contributes to the silencing of off-target genes and repetitive sequences in Caenorhabditis elegans.
Journal Genetics
Abstract Small RNAs recognize, bind, and regulate other complementary cellular RNAs. The introduction of small RNAs to eukaryotic cells frequently results in unintended silencing of related, but not identical, RNAs: a process termed off-target gene silencing. Off-target gene silencing is one of the major concerns during the application of small RNA-based technologies for gene discovery and the treatment of human disease. Off-target gene silencing is commonly thought to be due to inherent biochemical limitations of the RNAi machinery. Here we show that following the introduction of exogenous sources of double-stranded RNA, the nuclear RNAi pathway, but not its cytoplasmic counterparts, is the primary source of off-target silencing in Caenorhabditis elegans. In addition, we show that during the normal course of growth and development the nuclear RNAi pathway regulates repetitive gene families. Therefore, we speculate that RNAi off-target effects might not be "mistakes" but rather an intentional and genetically programmed aspect of small RNA-mediated gene silencing, which might allow small RNAs to silence rapidly evolving parasitic nucleic acids. Finally, reducing off-target effects by manipulating the nuclear RNAi pathway in vivo might improve the efficacy of small RNA-based technologies.
Volume 197(1)
Pages 121-32
Published 2014-5
DOI 10.1534/genetics.113.159780
PII genetics.113.159780
PMID 24532782
PMC PMC4012473
MeSH Alleles Animals Base Sequence Caenorhabditis elegans / cytology* Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Nucleus / genetics* Genetic Loci / genetics RNA Interference* RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Repetitive Sequences, Nucleic Acid / genetics*
IF 3.564
Times Cited 5
C.elegans tm1120 tm1127 tm1195 tm1094 tm1414 tm2686 tm1019 tm1113 tm894 tm914 tm1200 tm1186 tm1116