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Regulation of de novo thymidylate biosynthesis by ubiquitination
Author(s) -
Eom Jae Yong,
Anderson Donald D,
Stover Patrick J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.892.5
Subject(s) - sumo protein , biosynthesis , thymidylate synthase , ubiquitin ligase , serine hydroxymethyltransferase , biochemistry , ubiquitin , de novo synthesis , methionine , degron , biology , serine , phosphoserine , microbiology and biotechnology , chemistry , amino acid , phosphorylation , enzyme , gene , genetics , cancer , fluorouracil
Folate‐mediated one‐carbon metabolism is required for the biosyntheses of purines, de novo thymidylate (dTMP), and S ‐adenosyl methionine. Deficiencies in folate and SNPs in folate‐utilizing enzymes are associated with developmental anomalies and diseases such as neural tube defects, cardiovascular disease, and cancer. The mechanisms underlying these, however, still remain unestablished. Our lab has shown that Serine hydroxymethyltransferase 1 (SHMT1) regulates the flux of one‐carbon units towards de novo dTMP biosynthesis at the expense of S ‐adenosyl methionine biosynthesis. The de novo dTMP biosynthetic pathway, which consists of SHMT1, SHMT2α, TYMS, and DHFR, is localized to the nucleus during S‐phase in a SUMO‐dependent manner. Here we show in SHMT1 SUMO‐site mutants, SHMT1 stability is increased and ubiquitination is inhibited. Furthermore, polyubiquitination of SHMT1 is absent in cytoplasmic fractions, but is greatly increased in nuclear fractions at G2/M‐phase, suggesting the degradation of SHMT1 occurs within the nucleus. These results suggest an antagonistic relationship between SHMT1 SUMOylation and ubiquitination, in which SUMOylation facilitates its nuclear import for de novo dTMP biosynthesis, while ubiquitination leads to degradation within the nucleus to turn off dTMP biosynthesis as cells progress into G1 phase.