RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type.
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Authors
Medhi, Ragini
Furlan, Giulia
Gorges, Beronia
Sapetschnig, Alexandra
Publication Date
2022-03Journal Title
RNA
ISSN
1355-8382
Publisher
Cold Spring Harbor Laboratory
Pages
rna.078976.121-rna.078976.121
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Medhi, R., Price, J., Furlan, G., Gorges, B., Sapetschnig, A., & Miska, E. (2022). RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type.. RNA, rna.078976.121-rna.078976.121. https://doi.org/10.1261/rna.078976.121
Abstract
The human terminal uridyl transferases TUT4 and TUT7 (TUT4/7) catalyze the additions of uridines at the 3' end of RNAs, including the precursors of the tumor suppressor miRNA let-7 upon recruitment by the oncoprotein LIN28A. As a consequence, let-7 family miRNAs are down-regulated. Disruption of this TUT4/7 activity inhibits tumorigenesis. Hence, targeting TUT4/7 could be a potential anticancer therapy. In this study, we investigate TUT4/7-mediated RNA regulation in two cancer cell lines by establishing catalytic knockout models. Upon TUT4/7 mutation, we observe a significant reduction in miRNA uridylation, which results in defects in cancer cell properties such as cell proliferation and migration. With the loss of TUT4/7-mediated miRNA uridylation, the uridylated miRNA variants are replaced by adenylated isomiRs. Changes in miRNA modification profiles are accompanied by deregulation of expression levels in specific cases. Unlike let-7s, most miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. Additionally, we identify TUT4/7-regulated cell-type-specific miRNA clusters and deregulation in their corresponding mRNA targets. Expression levels of miR-200c-3p and miR-141-3p are regulated by TUT4/7 in a cancer cell-type-specific manner. Subsequently, BCL2, which is a well-established target of miR-200c is up-regulated. Therefore, TUT4/7 loss causes deregulation of miRNA-mRNA networks in a cell-type-specific manner. Understanding of the underlying biology of such cell-type-specific deregulation will be an important aspect of targeting TUT4/7 for potential cancer therapies.
Keywords
LIN28A, RNA uridylation, TUT4, TUT7, let-7
Sponsorship
Wellcome Trust (219475/Z/19/Z)
Cancer Research UK (A27826)
Wellcome Trust (203144/Z/16/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Cancer Research UK (18583)
Identifiers
External DOI: https://doi.org/10.1261/rna.078976.121
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332865
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