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Loss of Lamin A leads to the nuclear translocation of AGO2 and compromised RNA interference

V. Lobo, I. Nowak, C. Fernandez, AI. Correa Muler, JO. Westholm, HC. Huang, I. Fabrik, HT. Huynh, E. Shcherbinina, M. Poyraz, A. Härtlova, D. Benhalevy, D. Angeletti, AA. Sarshad

. 2024 ; 52 (16) : 9917-9935. [pub] 20240909

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24018963

Grantová podpora
PAR 2020/228 Knut and Alice Wallenberg Foundation
2019-01855 Swedish Research Council
S19-0019 Swedish Society for Medical Research
CTS 19:5 Carl Trygger Foundation
SLS-934036 Swedish Medical Society
Emil och Vera Cornell Foundation
M18-0091 Ake Wiberg Foundation
2018-02791 Magnus Bergvall Foundation
FB18-109 Assar Gabrielssons Foundation
JS2019-0015 Jeansson Foundation
FB19-0063 Guvnor and Josef Anérs Foundation
Ollie and Elof Ericsson Foundation
193-614 Olle Engkvist Byggmästare Foundation
Knut and Alice Wallenberg Foundation
TAU Vice President for Research and Development Fund
2021.0033 Knut and Alice Wallenberg Fellow Program
2021-01164 Swedish Research Council
University of Gothenburg
B-DOMINANCE European Research Council - International

In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event; however, in the last decade, a growing number of reports convincingly show the nuclear localization of the Argonaute (AGO) proteins. Nevertheless, the extent of nuclear RNAi and its implication in biological mechanisms remain to be elucidated. We found that reduced Lamin A levels significantly induce nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 cells, evident by changes in cell morphology, increased cell proliferation, and oncogenic miRNA expression. Moreover, AGO fPAR-CLIP in Lamin A KO SHSY5Y cells revealed significantly reduced RNAi activity. Further exploration of the nuclear AGO interactome by mass spectrometry identified FAM120A, an RNA-binding protein and known interactor of AGO2. Subsequent FAM120A fPAR-CLIP, revealed that FAM120A co-binds AGO targets and that this competition reduces the RNAi activity. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, FAM120A mediated RNAi impairment, and upregulation of oncogenic miRNAs, facilitating cancer cell proliferation.

Citace poskytuje Crossref.org

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