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A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function

Nature Genetics volume 41, pages 365–370 (2009)Cite this article

A Retraction to this article was published on 27 January 2016

A Corrigendum to this article was published on 01 May 2010

This article has been updated

Abstract

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.

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Figure 1: A mutant TARBP2 in human cancer.
Figure 2: Transfection of wild-type TARBP2 rescues pre-miRNA processing capacity.
Figure 3: TARBP2 mutation impairs DICER1 protein.
Figure 4: Tumor suppressor features of the TRBP–DICER1 complex.

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Change history

  • 09 April 2010

    In the version of this article initially published, the colony formation assay image labeled “Co115.DICER1” was the incorrect image. The error has been corrected and a corrected version of Figure 4 panel e is provided in the HTML and PDF versions of the article.

  • 27 January 2016

    We have recently become aware of the presence of duplicated images in the Figures 3 and 4 and Supplementary Figures 5 and 6 in our publication Nat. Genet. 41, 365–370, 2009, that were assembled according to the specified author contributions. We therefore retract the publication for the sake of the high standards we expect for research and scientific journals. All the authors have signed this statement.

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Acknowledgements

This work was supported by Grants SAF2007-00027-65134, FIS PI08-0517, Consolider CSD2006-49 and CANCERDIP FP7-200620. S.A.M. is a research fellow of the FCT-Foundation Science and Technology Portugal SFRH/BD/15900/2005 GABBA 2005 PhD program. M.E. is an ICREA Research Professor.

Author information

Authors and Affiliations

  1. Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain

    Sonia A Melo, Santiago Ropero, Catia Moutinho, Agustin F Fernandez, Bibiana Ferreira & Manel Esteller

  2. Department of Medical Genetics, Tumor Genomics Group, Academy of Finland and Genome-Scale Biology Research Program/Biomedicum, University of Helsinki, Helsinki, F-00014, Finland

    Lauri A Aaltonen

  3. Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan

    Hiroyuki Yamamoto

  4. Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Houston, 77030, Texas, USA

    George A Calin, Simona Rossi & Chang-Gong Liu

  5. Medical Faculty of the University of Porto and Hospital S. João and Institute of Molecular Pathology and Immunology (IPATIMUP), Porto, 4200-465, Portugal

    Fatima Carneiro & Carla Oliveira

  6. Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, Barcelona, 08907, Spain

    Alberto Villanueva & Gabriel Capella

  7. Molecular Biology and Biochemistry Research Center for Nanomedicine, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Barcelona, 08035, Catalonia, Spain

    Simo Schwartz Jr

  8. Center for Genomic Regulation, C/Dr. Aiguader 88, Barcelona, 08003, Catalonia, Spain

    Ramin Shiekhattar

  9. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, 08010, Catalonia, Spain

    Ramin Shiekhattar & Manel Esteller

  10. Cancer Epigenetics and Biology Program (PEBC), Catalan Institute of Oncology (ICO), Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), 08907 L'Hospitalet, Barcelona, Catalonia, Spain

    Manel Esteller

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Contributions

S.A.M., S. Ropero and M.E., study and experimental design; C.M. and A.F.F., genomic sequencing; G.A.C., S. Rossi and C.-G.L., microRNAarray hybridization and statistical analysis; B.F., FISH experiments; A.V., animal experiments. L.A.A., H.Y., F.C., C.O., G.C., S.S. and R.S. provided essential reagents, biological samples and intellectual support; S.A.M. and M.E. wrote the manuscript.

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Correspondence to Manel Esteller.

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Supplementary Table 1 and Supplementary Figures 1–7 (PDF 1701 kb)

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Melo, S., Ropero, S., Moutinho, C. et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet 41, 365–370 (2009). https://doi.org/10.1038/ng.317

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