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 journalArticlepeer-review

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 languageEnglish
Pages (from-to)303-315
Number of pages13
JournalCancer Cell
Volume18
Issue number4
DOIs
Publication statusPublished - Oct 19 2010

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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