A genetic defect in exportin-5 traps precursor MicroRNAs in the nucleus of cancer cells

Sonia A. Melo; Catia Moutinho; Santiago Ropero; George A. Calin; Simona Rossi; Riccardo Spizzo; Agustin F. Fernandez; Veronica Davalos; Alberto Villanueva; Guillermo Montoya; Hiroyuki Yamamoto; Simo Schwartz; Manel Esteller

doi:10.1016/j.ccr.2010.09.007

A genetic defect in exportin-5 traps precursor MicroRNAs in the nucleus of cancer cells

Sonia A. Melo, Catia Moutinho, Santiago Ropero, George A. Calin, Simona Rossi, Riccardo Spizzo, Agustin F. Fernandez, Veronica Davalos, Alberto Villanueva, Guillermo Montoya, Hiroyuki Yamamoto, Simo Schwartz, Manel Esteller

Research output: Contribution to journal › Article › peer-review

279 Scopus citations

Abstract

The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features.

Original language	English (US)
Pages (from-to)	303-315
Number of pages	13
Journal	Cancer cell
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2010.09.007
State	Published - Oct 19 2010

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2010.09.007

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title = "A genetic defect in exportin-5 traps precursor MicroRNAs in the nucleus of cancer cells",

abstract = "The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features.",

author = "Melo, {Sonia A.} and Catia Moutinho and Santiago Ropero and Calin, {George A.} and Simona Rossi and Riccardo Spizzo and Fernandez, {Agustin F.} and Veronica Davalos and Alberto Villanueva and Guillermo Montoya and Hiroyuki Yamamoto and Simo Schwartz and Manel Esteller",

note = "Funding Information: Supported by Grant PI08-1345, Consolider MEC09-05, and Dr. Josef Steiner Cancer Research Foundation. S.A.M. is a research fellow of the FCT-Foundation Science and Technology Portugal SFRH/BD/15900/2005 GABBA 2005 PhD program. G.A.C. is supported by The University of Texas M.D. Anderson Research Trust, University of Texas System Regents Research Scholar, Ladjevardian Regents Research Scholar Fund, and NIH grant 1R01CA135444. ",

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AU - Melo, Sonia A.

AU - Moutinho, Catia

AU - Ropero, Santiago

AU - Calin, George A.

AU - Rossi, Simona

AU - Spizzo, Riccardo

AU - Fernandez, Agustin F.

AU - Davalos, Veronica

AU - Villanueva, Alberto

AU - Montoya, Guillermo

AU - Yamamoto, Hiroyuki

AU - Schwartz, Simo

AU - Esteller, Manel

N1 - Funding Information: Supported by Grant PI08-1345, Consolider MEC09-05, and Dr. Josef Steiner Cancer Research Foundation. S.A.M. is a research fellow of the FCT-Foundation Science and Technology Portugal SFRH/BD/15900/2005 GABBA 2005 PhD program. G.A.C. is supported by The University of Texas M.D. Anderson Research Trust, University of Texas System Regents Research Scholar, Ladjevardian Regents Research Scholar Fund, and NIH grant 1R01CA135444.

PY - 2010/10/19

Y1 - 2010/10/19

N2 - The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features.

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A genetic defect in exportin-5 traps precursor MicroRNAs in the nucleus of cancer cells

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