A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function.
microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation. Explanations for this observation include a failure of miRNA post-transcriptional regulation, transcriptional silencing associated with hypermethylation of CpG island promoters and miRNA transcriptional repression by oncogenic factors. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation. However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex, in sporadic and hereditary carcinomas with microsatellite instability. The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.
Melo
Sonia A
SA
Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
Ropero
Santiago
S
Moutinho
Catia
C
Aaltonen
Lauri A
LA
Yamamoto
Hiroyuki
H
Calin
George A
GA
Rossi
Simona
S
Fernandez
Agustin F
AF
Carneiro
Fatima
F
Oliveira
Carla
C
Ferreira
Bibiana
B
Liu
Chang-Gong
CG
Villanueva
Alberto
A
Capella
Gabriel
G
Schwartz
Simo
S
Shiekhattar
Ramin
R
Esteller
Manel
M
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D043244:Ribonuclease III / Q000502:physiology*; D014162:Transfection; D000099253:Trans-Activation Responsive RNA-Binding Protein
D053487:DEAD-box RNA Helicases; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; D000099253:Trans-Activation Responsive RNA-Binding Protein; C408087:DICER1 protein, human