The RNA exosome component hRrp6 is a target for 5-fluorouracil in human cells.
The drug 5-fluorouracil (5-FU) is a widely used chemotherapeutic in the treatment of solid tumors. Recently, the essential 3'-5' exonucleolytic multisubunit RNA exosome was implicated as a target for 5-FU in yeast. Here, we show that this is also the case in human cells. HeLa cells depleted of the inessential exosome component hRrp6, also called PM/Scl100, are significantly growth impaired relative to control cells after 5-FU administration. The selective stabilization of bona fide hRrp6 RNA substrates on 5-FU treatment suggests that this exosome component is specifically targeted. Consistently, levels of hRrp6 substrates are increased in two 5-FU-sensitive cell lines. Interestingly, whereas down-regulation of all tested core exosome components results in decreased hRrp6 levels, depletion of hRrp6 leaves levels of other exosome components unchanged. Taken together, our data position hRrp6 as a promising target for antiproliferative intervention.
Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology, University of Aarhus, CF Møllers Alle, Building 1130, 8000 Aarhus C., Denmark.
Susanne
S
Kammler
Søren
S
Lykke-Andersen
Torben Heick
TH
Jensen
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D020077:Endogenous Retroviruses / Q000235:genetics; D005095:Exoribonucleases / Q000037:antagonists & inhibitors* / Q000235:genetics; D063326:Exosome Multienzyme Ribonuclease Complex; D005472:Fluorouracil / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D009687:Nuclear Proteins; D012333:RNA, Messenger; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; C077044:EXOSC10 protein, human; D005472:Fluorouracil