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


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.
Anderson
Donald D
DD
Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
Woeller
Collynn F
CF
Stover
Patrick J
PJ
D000595:Amino Acid Sequence; D015153:Blotting, Western; D006801:Humans; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000737:chemistry / Q000378:metabolism*
D011994:Recombinant Proteins; D025842:SUMO-1 Protein; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase