TY - JOUR
T1 - Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer
T2 - The Case of Editing in RNA-Binding Motif Protein 8A
AU - Abukar, Asra
AU - Wipplinger, Martin
AU - Hariharan, Ananya
AU - Sun, Suna
AU - Ronner, Manuel
AU - Sculco, Marika
AU - Okonska, Agata
AU - Kresoja-Rakic, Jelena
AU - Rehrauer, Hubert
AU - Qi, Weihong
AU - Beusechem, Victor W van
AU - Felley-Bosco, Emanuela
N1 - Funding Information: Funding: This work was supported by Swiss National Science Foundation, grant 320030_182690, Walter-Bruckerhoff Stiftung and Stiftung für Angewandte Krebsforchung; Suna Sun is supported by China Scholarship Council (CSC). MS was supported by the HERMES (HEreditary Risk in MESothelioma) Project, funded by the offer of compensation to the inhabitants of Casale Monferrato deceased or affected by mesothelioma. Funding Information: This work was supported by Swiss National Science Foundation, grant 320030_182690, Walter-Bruckerhoff Stiftung and Stiftung f?r Angewandte Krebsforchung; Suna Sun is supported by China Scholarship Council (CSC). MS was supported by the HERMES (HEreditary Risk in MESothelioma) Project, funded by the offer of compensation to the inhabitants of Casale Monferrato deceased or affected by mesothelioma. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3'UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3'UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts.
AB - Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3'UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3'UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts.
KW - Adenosine deaminase acting on dsRNA
KW - Mesothelioma
KW - Musashi
KW - RNA editing
KW - RNA-binding motif protein 8a
KW - RNA-binding proteins
UR - http://www.scopus.com/inward/record.url?scp=85121110782&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells10123543
DO - https://doi.org/10.3390/cells10123543
M3 - Article
C2 - 34944051
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 12
M1 - 3543
ER -