The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells

Cancer cells reprogramme one‐carbon metabolism (OCM) to sustain growth and proliferation. Depending on cell demands, serine hydroxymethyltransferase (SHMT) dynamically changes the fluxes of OCM by reversibly converting serine and tetrahydrofolate (THF) into 5,10‐methylene‐THF and glycine. SHMT is a...

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Published in:The FEBS journal 2018-09, Vol.285 (17), p.3238-3253
Main Authors: Giardina, Giorgio, Paone, Alessio, Tramonti, Angela, Lucchi, Roberta, Marani, Marina, Magnifico, Maria Chiara, Bouzidi, Amani, Pontecorvi, Valentino, Guiducci, Giulia, Zamparelli, Carlotta, Rinaldo, Serena, Paiardini, Alessandro, Contestabile, Roberto, Cutruzzolà, Francesca
Format: Article
Language:English
Subjects:
Cancer
Catalysis
Catalytic activity
Cell proliferation
Crosstalk
Cytosol
Enzymes
Fluxes
Glycine
Isoforms
Localization
Lung cancer
Metabolism
Mitochondria
Mutants
Mutation
Nuclei (cytology)
OCM
PPI
quaternary structure
Serine
SGOCM
Synthesis
Tetrahydrofolic acid
tetramer
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Summary:Cancer cells reprogramme one‐carbon metabolism (OCM) to sustain growth and proliferation. Depending on cell demands, serine hydroxymethyltransferase (SHMT) dynamically changes the fluxes of OCM by reversibly converting serine and tetrahydrofolate (THF) into 5,10‐methylene‐THF and glycine. SHMT is a tetrameric enzyme that mainly exists in three isoforms; two localize in the cytosol (SHMT1/SHMT2α) and one (SHMT2) in the mitochondria. Both the cytosolic isoforms can also translocate to the nucleus to sustain de novo thymidylate synthesis and support cell proliferation. Finally, the expression levels of the different isoforms are regulated to a certain extent by a yet unknown crosstalk mechanism. We have designed and fully characterized a set of three SHMT1 mutants, which uncouple the oligomeric state of the enzyme from its catalytic activity. We have then investigated the effects of the mutations on SHMT1 nuclear localization, cell viability and crosstalk in lung cancer cells (A549; H1299). Our data reveal that in these cell lines de novo thymidylate synthesis requires SHMT1 to be active, regardless of its oligomeric state. We have also confirmed that the crosstalk between the cytosolic and mitochondrial SHMT actually takes place and regulates the expression of the two isoforms. Apparently, the crosstalk mechanism is independent from the oligomeric state and the catalytic activity of SHMT1. Database Structural data are available in the PDB under the accession number 6FL5 We designed a set of three serine hydroxymethyltransferase 1 (SHMT1) mutants to uncouple the oligomeric state of the enzyme from its catalytic activity. We investigated the effects of these mutations on nuclear localization, cell viability, and crosstalk between SHMT1 and SHMT2 in lung cancer cells. In these cell lines, de novo thymidylate synthesis requires SHMT1 to be active regardless of its oligomeric state.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.14610