Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets.
Ribonuclease Dicer functions in cells to excise microRNAs from their precursors and process long double-stranded RNAs into short interfering RNAs. We show that transcripts containing long hairpin structures composed of CNG repeats are another class of Dicer targets. The cellular levels of transcripts from mutant genes involved in triplet repeat expansion diseases such as myotonic dystrophy type 1, Huntington's disease, and spinocerebellar ataxia type 1 are under Dicer control. The Dicer-induced downregulation of the mutant transcript in myotonic dystrophy cells is accompanied by the downregulation of transcripts containing long complementary repeats. Short CUG repeats generated from long repeat hairpins act as siRNAs and use the RNA interference pathway to trigger the downstream silencing effects. We demonstrate that synthetic oligonucleotides composed of repeats are highly specific in the silencing of mutant transcripts containing complementary repeats and may be considered as potential therapeutic agents.
Krol
Jacek
J
Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
Fiszer
Agnieszka
A
Mykowska
Agnieszka
A
Sobczak
Krzysztof
K
de Mezer
Mateusz
M
Krzyzosiak
Wlodzimierz J
WJ
D001483:Base Sequence; D015536:Down-Regulation / Q000235:genetics; D020868:Gene Silencing; D006367:HeLa Cells; D020271:Heredodegenerative Disorders, Nervous System / Q000201:enzymology; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000378:metabolism; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D013379:Substrate Specificity; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D009711:Nucleotides; D018075:RNA, Complementary; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043244:Ribonuclease III