title: Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis.
abstract: The de novo thymidylate biosynthetic pathway in mammalian cells translocates to the nucleus for DNA replication and repair and consists of the enzymes serine hydroxymethyltransferase 1 and 2α (SHMT1 and SHMT2α), thymidylate synthase, and dihydrofolate reductase. In this study, we demonstrate that this pathway forms a multienzyme complex that is associated with the nuclear lamina. SHMT1 or SHMT2α is required for co-localization of dihydrofolate reductase, SHMT, and thymidylate synthase to the nuclear lamina, indicating that SHMT serves as scaffold protein that is essential for complex formation. The metabolic complex is enriched at sites of DNA replication initiation and associated with proliferating cell nuclear antigen and other components of the DNA replication machinery. These data provide a mechanism for previous studies demonstrating that SHMT expression is rate-limiting for de novo thymidylate synthesis and indicate that de novo thymidylate biosynthesis occurs at replication forks.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anderson
authors.forename: Collynn F
authors.initials: CF
authors.lastname: Woeller
authors.forename: En-Pei
authors.initials: EP
authors.lastname: Chiang
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D004247:DNA / Q000096:biosynthesis* / Q000235:genetics; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication / Q000502:physiology*; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D034881:Nuclear Lamina / Q000201:enzymology* / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D013938:Thymidine Monophosphate; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human