Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase.

Abstract

BACKGROUND Impairments in folate-mediated one-carbon metabolism are associated with pathologies and developmental anomalies, including cardiovascular disease, cancer, neurological disorders and neural tube defects. The mechanisms that detail the role of folate and one-carbon metabolism in these disorders remain to be established. Folate deficiency impairs folate-dependent thymidylate biosynthesis resulting in depleted dTTP levels, increased rates of uracil incorporation into DNA and genomic instability. Folate-dependent enzymes involved in the de novo thymidylate pathway include cytoplasmic serine hydroxymethyltransferase (cSHMT), thymidylate synthase (TS) and dihydrofolate reductase (DHFR). Previously, we demonstrated that cSHMT-derived folate activated one-carbon units are preferentially incorporated into thymidylate, and we provided evidence that this was achieved through modification with small ubiquitin-like modifier (SUMO) enabling SUMO-dependent nuclear localization of cSHMT during S-phase. METHODS AND RESULTS Here, we provide evidence that TS and DHFR are also substrates for UBC9-catalyzed SUMOylation in vitro by SUMO-1. CONCLUSIONS The SUMOylation of cSHMT, TS and DHFR provides a mechanism by which all three enzymes in the thymidylate synthesis pathway are directed and compartmentalized in the nucleus.

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@article{Anderson2007SmallUM, title={Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase.}, author={Donald D. Anderson and Collynn F. Woeller and Patrick J Stover}, journal={Clinical chemistry and laboratory medicine}, year={2007}, volume={45 12}, pages={1760-3} }