The non-coding RNA of the multidrug resistance-linked vault particle encodes multiple regulatory small RNAs.
Vault particles are conserved organelles implicated in multidrug resistance and intracellular transport. They contain three different proteins and non-coding vault RNAs (vRNAs). Here we show that human vRNAs produce several small RNAs (svRNAs) by mechanisms different from those in the canonical microRNA (miRNA) pathway. At least one of these svRNAs, svRNAb, associates with Argonaute proteins to guide sequence-specific cleavage and regulate gene expression similarly to miRNAs. We demonstrate that svRNAb downregulates CYP3A4, a key enzyme in drug metabolism. Our findings expand the repertoire of small regulatory RNAs and assign, for the first time, a function to vRNAs that may help explain the association between vault particles and drug resistance.
Persson
Helena
H
Department of Oncology and CREATE Health Strategic Centre for Clinical Cancer Research, Lund University, BMC, 221 84 Lund, Sweden.
Kvist
Anders
A
Vallon-Christersson
Johan
J
Medstrand
Patrik
P
Borg
Ake
A
Rovira
Carlos
C
D060565:Argonaute Proteins; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics / Q000502:physiology*
C466422:AGO2 protein, human; C517143:AGO3 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D035683:MicroRNAs; D012333:RNA, Messenger; D022661:RNA, Untranslated; D020394:Vault Ribonucleoprotein Particles; D012313:RNA; C517918:DROSHA protein, human; D043244:Ribonuclease III