Premium
Reduced SHMT2 expression and serine/glycine ratio affect mtDNA (736.7)
Author(s) -
Alonzo Judith,
Stover Patrick
Publication year - 2014
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.28.1_supplement.736.7
Subject(s) - serine hydroxymethyltransferase , serine , biochemistry , uracil , thymidylate synthase , glycine , biosynthesis , biology , mitochondrial dna , dna synthesis , mitochondrion , microbiology and biotechnology , dna , gene , phosphorylation , genetics , amino acid , fluorouracil , chemotherapy
Maintaining proper nucleotide balance is required to avoid genome instability, for both mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA). Mitochondrial deoxynucleotide triphosphates (dNTPs) are obtained from either salvage or de novo biosynthesis pathways. De novo biosynthesis of thymidylate and purines is folate‐dependent. De novo thymidylate (dTMP) biosynthesis has been shown to occur within mitochondria for mtDNA synthesis and the nucleus for nuDNA synthesis. Disruption of nuclear de novo dTMP biosynthesis affects genome integrity and increases uracil levels in DNA. In mitochondria, de novo dTMP biosynthesis requires serine hydroxymethyltransferase 2 (SHMT2), which transfers a one‐carbon unit from serine to tetrahydrofolate (THF), producing 5,10‐methyleneTHF and glycine; 5‐10‐methyleneTHF is then utilized by thymidylate synthase to generate dTMP from dUMP. In the nucleus, SHMT expression is limiting in de novo dTMP biosynthesis, and reduced SHMT expression elevates uracil content in nuDNA. We are investigating effects of reduced SHMT2 expression and alterations in the cellular serine/glycine ratio on mtDNA content, mitochondria mass, and uracil levels in mtDNA in HeLa cells. Preliminary data indicate that reduced SHMT2 expression and serine and glycine ratio affect mtDNA content and mtDNA integrity. Grant Funding Source : Supported by NIH R37DK58144