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

Minakshi Gandhi, Matthias Groß, Jessica M. Holler, Si’Ana A. Coggins, Nitin Patil, Joerg H. Leupold, Mathias Munschauer, Monica Schenone, Christina R. Hartigan, Heike Allgayer, Baek Kim and Sven Diederichs ()
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Minakshi Gandhi: German Cancer Research Center (DKFZ)
Matthias Groß: German Cancer Research Center (DKFZ)
Jessica M. Holler: Emory University
Si’Ana A. Coggins: Emory University
Nitin Patil: University of Heidelberg
Joerg H. Leupold: University of Heidelberg
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: University of Heidelberg
Baek Kim: Emory University
Sven Diederichs: German Cancer Research Center (DKFZ)

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17007-9

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