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The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells
Author(s) -
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
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14610
Subject(s) - serine hydroxymethyltransferase , serine , biochemistry , cytosol , cell growth , enzyme , glycine , biology , cancer cell , chemistry , amino acid , cancer , genetics
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 ( SHMT 1/ SHMT 2α) and one ( SHMT 2) 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 SHMT 1 mutants, which uncouple the oligomeric state of the enzyme from its catalytic activity. We have then investigated the effects of the mutations on SHMT 1 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 SHMT 1 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 SHMT 1. Database Structural data are available in the PDB under the accession number 6FL5