MiR-34a Directly Targets TRNA Precursors and Affects Cellular Proliferation, Cell Cycle, and Apoptosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jun 27

PMID 29941603

Citations 32

Authors

Bo Wang

Dongping Li

Igor Kovalchuk

Ingrid J Apel

Arul M Chinnaiyan

Rafal K Woycicki

Charles R Cantor

Olga Kovalchuk

Affiliations

Soon will be listed here.

Abstract

It remains unknown whether microRNA (miRNA/miR) can target transfer RNA (tRNA) molecules. Here we provide evidence that miR-34a physically interacts with and functionally targets tRNA precursors in both in vitro pulldown and Argonaute 2 (AGO2) cleavage assays. We find that miR-34a suppresses breast carcinogenesis, at least in part by lowering the levels of tRNA through AGO2-mediated repression, consequently inhibiting the proliferation of breast cancer cells and inducing cell cycle arrest and apoptosis. Moreover, miR-34a expression is negatively correlated with tRNA levels in cancer cell lines. Furthermore, we find that tRNA knockdown also reduces cell proliferation while inducing cell cycle arrest and apoptosis. Conversely, ectopic expression of tRNA promotes cell proliferation, inhibits apoptosis, and accelerates the S/G2 transition. Moreover, the enforced expression of modified tRNA completely restores the phenotypic changes induced by miR-34a. Our results demonstrate that miR-34a directly targets tRNA precursors via AGO2-mediated cleavage, and that tRNA functions as an oncogene, potentially representing a target molecule for therapeutic intervention.

Citing Articles

The crosstalk between non-coding RNAs and cell-cycle events: A new frontier in cancer therapy.

Pathania A, Chava H, Balusu R, Pasupulati A, Coulter D, Challagundla K Mol Ther Oncol. 2024; 32(2):200785.

PMID: 38595981 PMC: 10973673. DOI: 10.1016/j.omton.2024.200785.

Selective Occupation by E2F and RB of Loci Expressed by RNA Polymerase III.

Sizer R, Butterfield S, Hancocks L, Gato De Sousa L, White R Cancers (Basel). 2024; 16(3).

PMID: 38339234 PMC: 10854548. DOI: 10.3390/cancers16030481.

miRNA expression in PCOS: unveiling a paradigm shift toward biomarker discovery.

Rashid G, Khan N, Elsori D, Youness R, Hassan H, Siwan D Arch Gynecol Obstet. 2024; 309(5):1707-1723.

PMID: 38316651 DOI: 10.1007/s00404-024-07379-4.

Transfer RNAs as dynamic and critical regulators of cancer progression.

Pinzaru A, Tavazoie S Nat Rev Cancer. 2023; 23(11):746-761.

PMID: 37814109 DOI: 10.1038/s41568-023-00611-4.

Selection of tRNA Genes in Human Breast Tumours Varies Substantially between Individuals.

Butterfield S, Sizer R, Rand E, White R Cancers (Basel). 2023; 15(14).

PMID: 37509247 PMC: 10377016. DOI: 10.3390/cancers15143576.

References

Romero-Lopez C, Berzal-Herranz A . A long-range RNA-RNA interaction between the 5' and 3' ends of the HCV genome. RNA. 2009; 15(9):1740-52. PMC: 2743058. DOI: 10.1261/rna.1680809. View

Tuller T . The Effect of Dysregulation of tRNA Genes and Translation Efficiency Mutations in Cancer and Neurodegeneration. Front Genet. 2012; 3:201. PMC: 3469790. DOI: 10.3389/fgene.2012.00201. View

Winter J, Roepcke S, Krause S, Muller E, Otto A, Vingron M . Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines. PLoS One. 2008; 3(7):e2780. PMC: 2474680. DOI: 10.1371/journal.pone.0002780. View

Corney D, Hwang C, Matoso A, Vogt M, Flesken-Nikitin A, Godwin A . Frequent downregulation of miR-34 family in human ovarian cancers. Clin Cancer Res. 2010; 16(4):1119-28. PMC: 2822884. DOI: 10.1158/1078-0432.CCR-09-2642. View

Guo H, Ingolia N, Weissman J, Bartel D . Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010; 466(7308):835-40. PMC: 2990499. DOI: 10.1038/nature09267. View

Calin G, Sevignani C, Dumitru C, Hyslop T, Noch E, Yendamuri S . Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004; 101(9):2999-3004. PMC: 365734. DOI: 10.1073/pnas.0307323101. View

Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A . Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 2007; 6(13):1586-93. DOI: 10.4161/cc.6.13.4436. View

Xu K, Lin J, Zandi R, Roth J, Ji L . MicroRNA-mediated target mRNA cleavage and 3'-uridylation in human cells. Sci Rep. 2016; 6:30242. PMC: 4954961. DOI: 10.1038/srep30242. View

Maniataki E, Mourelatos Z . A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005; 19(24):2979-90. PMC: 1315402. DOI: 10.1101/gad.1384005. View

10.

Chang T, Wentzel E, Kent O, Ramachandran K, Mullendore M, Lee K . Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007; 26(5):745-52. PMC: 1939978. DOI: 10.1016/j.molcel.2007.05.010. View

11.

Lim L, Lau N, Garrett-Engele P, Grimson A, Schelter J, Castle J . Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433(7027):769-73. DOI: 10.1038/nature03315. View

12.

Berns A . A tRNA with oncogenic capacity. Cell. 2008; 133(1):29-30. DOI: 10.1016/j.cell.2008.03.017. View

13.

Wu N, Zhao X, Liu M, Liu H, Yao W, Zhang Y . Role of microRNA-26b in glioma development and its mediated regulation on EphA2. PLoS One. 2011; 6(1):e16264. PMC: 3021542. DOI: 10.1371/journal.pone.0016264. View

14.

Maniataki E, Mourelatos Z . Human mitochondrial tRNAMet is exported to the cytoplasm and associates with the Argonaute 2 protein. RNA. 2005; 11(6):849-52. PMC: 1370769. DOI: 10.1261/rna.2210805. View

15.

Bernardo B, Gao X, Winbanks C, Boey E, Tham Y, Kiriazis H . Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A. 2012; 109(43):17615-20. PMC: 3491509. DOI: 10.1073/pnas.1206432109. View

16.

Wang B, Li D, Kovalchuk O . p53 Ser15 phosphorylation and histone modifications contribute to IR-induced miR-34a transcription in mammary epithelial cells. Cell Cycle. 2013; 12(13):2073-83. PMC: 3737310. DOI: 10.4161/cc.25135. View

17.

Macfarlane L, Murphy P . MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2011; 11(7):537-61. PMC: 3048316. DOI: 10.2174/138920210793175895. View

18.

Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner M, Pan T . tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009; 37(21):7268-80. PMC: 2790902. DOI: 10.1093/nar/gkp787. View

19.

Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N . Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007; 26(5):731-43. DOI: 10.1016/j.molcel.2007.05.017. View

20.

Motorin Y, Helm M . tRNA stabilization by modified nucleotides. Biochemistry. 2010; 49(24):4934-44. DOI: 10.1021/bi100408z. View