Plant Physiol. Drug Metab Dispos
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Published on October 17, 2008; 10.1104/pp.108.130336

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Received September 25, 2008
Accepted October 15, 2008

A genome-wide and metabolic analysis determined the adaptive response of Arabidopsis cells to folate depletion induced by methotrexate

Karen Loizeau , Veerle De Brouwer , Bernadette Gambonnet , Agnes Yu , Jean-Pierre Renou , Dominique Van Der Straeten , Willy E. Lambert , Fabrice Rebeille , and Stephane Ravanel *

Laboratoire de Physiologie Cellulaire Vegetale, UMR5168 CNRS-CEA-INRA-Universite Joseph Fourier Grenoble I, Institut de Recherches en Technologies et Sciences pour le Vivant, CEA-Grenoble, 17 rue des Martyrs, F-38054 Grenoble Cedex 9, France, Laboratory of Toxicology, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium, UMR INRA1165 CNRS8114 UEVE, Unite de Recherche en Genomique Vegetale, 2 rue Gaston Cremieux, CP5708, F-91057 Evry, France, Unit Plant Hormone Signaling and Bio-imaging, Department of Molecular Genetics, Ghent University, K.L. Ledeganckstraat 35, B-9000 Ghent, Belgium

* Corresponding author; email: sravanel{at}cea.fr.

Control of folate homeostasis is essential to sustain the demand for one-carbon (C1) units that are necessary for major biological functions, including nucleotide synthesis and methylation reactions. In this study we analyzed the genome-wide and metabolic adaptive response of Arabidopsis thaliana cells to folate depletion induced by the antifolate methotrexate. Drug treatment induced a response typical to xenobiotic stress and important changes in folate content and composition. This resulted in a reduction of cell division and primary energy metabolism that was likely associated with perturbation of nucleotide homeostasis. Through a modification of serine metabolism, folate depletion also induced O-acetylserine accumulation and mimicked sulfur-deficiency response. The major adaptive response to folate limitation concerned the composition of the folate pool rather than the intracellular level of cofactors. Thus, no significant change in the expression of genes involved in cofactor synthesis, degradation or trafficking was observed. However, changes in the distribution of C1-derivatives pools and increased expression levels for transcripts coding enzymes manipulating C1-moieties in plastids suggested a re-orientation of C1-units towards the synthesis of purine and thymidylate. Also, no genomic or metabolic adaptation was built up to counterbalance the major impairment of the methyl index, which controls the efficiency of methylation reactions in the cell. Together, these data suggested that the metabolic priority of Arabidopsis cells in response to folate limitation was to shuttle the available folate derivatives to the synthesis of nucleotides at the expense of methylation reactions.




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