title: Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis.
abstract: Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)- and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As2O3), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As2O3exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As2O3inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As2O3-induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Elena
authors.initials: E
authors.lastname: Kamynina
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.|Graduate Field of Biology and Biomedical Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Erica R
authors.initials: ER
authors.lastname: Lachenauer
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Aislyn C
authors.initials: AC
authors.lastname: DiRisio
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Liebenthal
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Field
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853; PJS13@cornell.edu.|Graduate Field of Biology and Biomedical Sciences, Cornell University, Ithaca, NY 14853.|Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000619:Aminohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005574:Formate-Tetrahydrofolate Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability / Q000187:drug effects; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D059748:Proteolysis; D025841:Small Ubiquitin-Related Modifier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D013938:Thymidine Monophosphate / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014498:Uracil / Q000378:metabolism
chemical_list: D001152:Arsenicals; D009097:Multienzyme Complexes; D010087:Oxides; D025841:Small Ubiquitin-Related Modifier Proteins; D013938:Thymidine Monophosphate; D014498:Uracil; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase; D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase; D000077237:Arsenic Trioxide
keywords: MTHFD1; SUMO-1; arsenic trioxide; genome instability; one-carbon metabolism