Nature Genetics 41, 365 - 370 (2009)
Published online: 15 February 2009 |
A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function
Sonia A Melo1, Santiago Ropero1, Catia Moutinho1, Lauri A Aaltonen2, Hiroyuki Yamamoto3, George A Calin4, Simona Rossi4, Agustin F Fernandez1, Fatima Carneiro5, Carla Oliveira5, Bibiana Ferreira1, Chang-Gong Liu4, Alberto Villanueva6, Gabriel Capella6, Simo Schwartz Jr7, Ramin Shiekhattar8,9 & Manel Esteller1,9,10
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 downregulation1, 2, 3. Explanations for this observation include a failure of miRNA post-transcriptional regulation4, transcriptional silencing associated with hypermethylation of CpG island promoters5, 6, 7 and miRNA transcriptional repression by oncogenic factors8. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation9. 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 complex10, 11, in sporadic and hereditary carcinomas with microsatellite instability12, 13, 14. 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.