Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells

Maddocks, O. D.K. , Labuschagne, C. F., Adams, P. D. and Vousden, K. H. (2016) Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Molecular Cell, 61(2), pp. 210-221. (doi:10.1016/j.molcel.2015.12.014) (PMID:26774282) (PMCID:PMC4728077)

Maddocks, O. D.K. , Labuschagne, C. F., Adams, P. D. and Vousden, K. H. (2016) Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Molecular Cell, 61(2), pp. 210-221. (doi:10.1016/j.molcel.2015.12.014) (PMID:26774282) (PMCID:PMC4728077)

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Abstract

Summary: Crosstalk between cellular metabolism and the epigenome regulates epigenetic and metabolic homeostasis and normal cell behavior. Changes in cancer cell metabolism can directly impact epigenetic regulation and promote transformation. Here we analyzed the contribution of methionine and serine metabolism to methylation of DNA and RNA. Serine can contribute to this pathway by providing one-carbon units to regenerate methionine from homocysteine. While we observed this contribution under methionine-depleted conditions, unexpectedly, we found that serine supported the methionine cycle in the presence and absence of methionine through de novo ATP synthesis. Serine starvation increased the methionine/S-adenosyl methionine ratio, decreasing the transfer of methyl groups to DNA and RNA. While serine starvation dramatically decreased ATP levels, this was accompanied by lower AMP and did not activate AMPK. This work highlights the difference between ATP turnover and new ATP synthesis and defines a vital function of nucleotide synthesis beyond making nucleic acids.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK grant C596/A10419 and ERC Grant 322842-METABOp53.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Adams, Professor Peter and Labuschagne, Dr Christiaan Fred and Maddocks, Dr Oliver and Vousden, Karen
Authors: Maddocks, O. D.K., Labuschagne, C. F., Adams, P. D., and Vousden, K. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cell
Publisher:Elsevier
ISSN:1097-2765
ISSN (Online):1097-4164
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Molecular Cell 61(2):210-221
Publisher Policy:Reproduced under a Creative Commons licence

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