The lncRNA lincNMR regulates nucleotide metabolism via a YBX1-RRM2 axis in cancer

• Type of Material: Article
• Authors: Minakshi Gandhi, German Cancer Research Center; Matthias Gross, German Cancer Research Center; Jessica M. Holler, Emory University; Si'Ana A. Coggins, Emory University; Nitin Patil, Heidelberg University; Joerg H. Leupold, Heidelberg University; Mathias Munschauer, Broad Institute of MIT and Harvard; Monica Schenone, Broad Institute of MIT and Harvard; Christina R. Hartigan, Broad Institute of MIT and Harvard; Heike Allgayer, Heidelberg University; Baek Kim, Emory University; Sven Diederichs, German Cancer Research Center
• Language: English
• Date: 2020-06-25
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17007-9
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 3214
• End Page: 3214
• Grant/Funding Information: Research in the B.K. lab is supported by NIH GM104198, R01 AI136581, and R01 AI150451 grants.; This project was funded by the Deutsche Forschungsgemeinschaft to S.D., DFG Di 1421/7-1.; M. Ga. was supported by a full doctoral scholarship from Deutscher Akademische Austauschdienst (DAAD).
• Keywords: Hallmarks; Survival; Human ribonucleotide reductase; Long noncoding RNAs; Science & Technology; Promotes; DNA-damage; Cells; Hydroxyurea; Multidisciplinary Sciences; Metastasis; Senescence; Science & Technology - Other Topics
• Research Categories: Engineering, Biomedical; Biology, Genetics; Biology, Cell; Health Sciences, Oncology

Abstract

Long intergenic non-coding RNA-Nucleotide Metabolism Regulator (lincNMR) is a long non-coding RNA (lncRNA) which is induced in hepatocellular carcinoma. Its depletion invokes a proliferation defect, triggers senescence and inhibits colony formation in liver, but also breast and lung cancer cells. Triple-label SILAC proteomics profiles reveal a deregulation of key cell cycle regulators in lincNMR-depleted cells like the key dNTP synthesizing enzymes RRM2, TYMS and TK1, implicating lincNMR in regulating nucleotide metabolism. LincNMR silencing decreases dNTP levels, while exogenous dNTPs rescues the proliferation defect induced by lincNMR depletion. In vivo RNA Antisense Purification (RAP-MS) identifies YBX1 as a direct interaction partner of lincNMR which regulates RRM2, TYMS and TK1 expression and binds to their promoter regions. In a Chick Chorioallantoic Membrane (CAM) in vivo model, lincNMR-depleted tumors are significantly smaller. In summary, we discover a lincRNA, lincNMR, which regulates tumor cell proliferation through a YBX1-RRM2-TYMS-TK1 axis governing nucleotide metabolism.