METTL1-mediated MG Modification of Arg-TCT TRNA Drives Oncogenic Transformation

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Aug 5

PMID 34352207

Citations 150

Authors

Esteban A Orellana

Qi Liu

Eliza Yankova

Mehdi Pirouz

Etienne De Braekeleer

Wencai Zhang

Jihoon Lim

Demetrios Aspris

Erdem Sendinc

Dimitrios A Garyfallos

Muxin Gu

Raja Ali

Alejandro Gutierrez

Sigitas Mikutis

Goncalo J L Bernardes

Eric S Fischer

Allan Bradley

George S Vassiliou

Frank J Slack

Konstantinos Tzelepis

Richard I Gregory

Affiliations

Soon will be listed here.

Abstract

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (mG) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of mG-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of mG-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.

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References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

Rapino F, Delaunay S, Rambow F, Zhou Z, Tharun L, de Tullio P . Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature. 2018; 558(7711):605-609. DOI: 10.1038/s41586-018-0243-7. View

Gingold H, Tehler D, Christoffersen N, Nielsen M, Asmar F, Kooistra S . A dual program for translation regulation in cellular proliferation and differentiation. Cell. 2014; 158(6):1281-1292. DOI: 10.1016/j.cell.2014.08.011. View

Lin S, Liu Q, Lelyveld V, Choe J, Szostak J, Gregory R . Mettl1/Wdr4-Mediated mG tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation. Mol Cell. 2018; 71(2):244-255.e5. PMC: 6086580. DOI: 10.1016/j.molcel.2018.06.001. View

Clarke C, Berg T, Birch J, Ennis D, Mitchell L, Cloix C . The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis. Curr Biol. 2016; 26(6):755-65. PMC: 4819511. DOI: 10.1016/j.cub.2016.01.045. View

Lin S, Liu Q, Jiang Y, Gregory R . Nucleotide resolution profiling of mG tRNA modification by TRAC-Seq. Nat Protoc. 2019; 14(11):3220-3242. PMC: 8959837. DOI: 10.1038/s41596-019-0226-7. View

Nedialkova D, Leidel S . Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity. Cell. 2015; 161(7):1606-18. PMC: 4503807. DOI: 10.1016/j.cell.2015.05.022. View

Frye M, Watt F . The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Curr Biol. 2006; 16(10):971-81. DOI: 10.1016/j.cub.2006.04.027. View

10.

Tian Q, Zhang M, Zeng J, Luo R, Wen Y, Chen J . METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN. J Mol Med (Berl). 2019; 97(11):1535-1545. DOI: 10.1007/s00109-019-01830-9. View

11.

Alexandrov A, Chernyakov I, Gu W, Hiley S, Hughes T, Grayhack E . Rapid tRNA decay can result from lack of nonessential modifications. Mol Cell. 2006; 21(1):87-96. DOI: 10.1016/j.molcel.2005.10.036. View

12.

Cozen A, Quartley E, Holmes A, Hrabeta-Robinson E, Phizicky E, Lowe T . ARM-seq: AlkB-facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments. Nat Methods. 2015; 12(9):879-84. PMC: 4553111. DOI: 10.1038/nmeth.3508. View

13.

de Crecy-Lagard V, Boccaletto P, Mangleburg C, Sharma P, Lowe T, Leidel S . Matching tRNA modifications in humans to their known and predicted enzymes. Nucleic Acids Res. 2019; 47(5):2143-2159. PMC: 6412123. DOI: 10.1093/nar/gkz011. View

14.

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson S . Promoter-bound METTL3 maintains myeloid leukaemia by mA-dependent translation control. Nature. 2017; 552(7683):126-131. PMC: 6217924. DOI: 10.1038/nature24678. View

15.

Santos M, Fidalgo A, Varanda A, Oliveira C, Santos M . tRNA Deregulation and Its Consequences in Cancer. Trends Mol Med. 2019; 25(10):853-865. DOI: 10.1016/j.molmed.2019.05.011. View

16.

Zinshteyn B, Gilbert W . Loss of a conserved tRNA anticodon modification perturbs cellular signaling. PLoS Genet. 2013; 9(8):e1003675. PMC: 3731203. DOI: 10.1371/journal.pgen.1003675. View

17.

Ishimura R, Nagy G, Dotu I, Zhou H, Yang X, Schimmel P . RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science. 2014; 345(6195):455-9. PMC: 4281038. DOI: 10.1126/science.1249749. View

18.

Liu Q, Shvarts T, Sliz P, Gregory R . RiboToolkit: an integrated platform for analysis and annotation of ribosome profiling data to decode mRNA translation at codon resolution. Nucleic Acids Res. 2020; 48(W1):W218-W229. PMC: 7319539. DOI: 10.1093/nar/gkaa395. View

19.

Begley U, Dyavaiah M, Patil A, Rooney J, DiRenzo D, Young C . Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol Cell. 2007; 28(5):860-70. PMC: 2211415. DOI: 10.1016/j.molcel.2007.09.021. View

20.

Lavallee V, Lemieux S, Boucher G, Gendron P, Boivin I, Armstrong R . RNA-sequencing analysis of core binding factor AML identifies recurrent ZBTB7A mutations and defines RUNX1-CBFA2T3 fusion signature. Blood. 2016; 127(20):2498-501. DOI: 10.1182/blood-2016-03-703868. View