Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis

J Biol Chem. 2012 Mar 2;287(10):7051-62. doi: 10.1074/jbc.M111.333120. Epub 2012 Jan 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA / biosynthesis*
  • DNA / genetics
  • DNA Repair / physiology
  • DNA Replication / physiology*
  • Glycine Hydroxymethyltransferase / genetics
  • Glycine Hydroxymethyltransferase / metabolism*
  • HeLa Cells
  • Humans
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Nuclear Lamina / enzymology*
  • Nuclear Lamina / metabolism
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Thymidine Monophosphate / biosynthesis*
  • Thymidine Monophosphate / genetics


  • Multienzyme Complexes
  • Thymidine Monophosphate
  • DNA
  • Tetrahydrofolate Dehydrogenase
  • Glycine Hydroxymethyltransferase
  • SHMT protein, human