A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells.
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.
Melo
Sonia A
SA
Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
Moutinho
Catia
C
Ropero
Santiago
S
Calin
George A
GA
Rossi
Simona
S
Spizzo
Riccardo
R
Fernandez
Agustin F
AF
Davalos
Veronica
V
Villanueva
Alberto
A
Montoya
Guillermo
G
Yamamoto
Hiroyuki
H
Schwartz
Simo
S
Esteller
Manel
M
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D028884:Karyopherins / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D012322:RNA Precursors / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism
D028884:Karyopherins; D035683:MicroRNAs; D050505:Mutant Proteins; D012322:RNA Precursors; D025521:Tumor Suppressor Proteins; C446511:XPO5 protein, human; D020931:ran GTP-Binding Protein