RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type
- Ragini Medhi1,2,
- Jonathan Price2,
- Giulia Furlan2,
- Beronia Gorges3,
- Alexandra Sapetschnig3 and
- Eric A. Miska1,2
- 1Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom
- 2Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom
- 3STORM Therapeutics Limited, Moneta Building, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom
- Corresponding author: eam29{at}cam.ac.uk
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
- Received September 16, 2021.
- Accepted December 2, 2021.
This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.