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Role of Trifunctional Enzyme MTHFD1 in Maintenance of DNA Stability
Author(s) -
Kamynina Elena,
Field Martha,
Stover Patrick
Publication year - 2015
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.29.1_supplement.919.16
Subject(s) - dna damage , dna repair , megaloblastic anemia , homocysteine , chemistry , biochemistry , dna , fibroblast , microbiology and biotechnology , biology , in vitro , vitamin b12
MTHFD1 is a trifunctional enzyme possessing methyleneTHF dehydrogenase (D), methenylTHF cyclohydrolase (C) and formylTHF synthetase (S) activities. We have recently demonstrated that MTHFD1 translocates to the nucleus in S phase where it plays a key enzymatic role providing one‐carbon units for dTMP synthesis. An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been recently identified. The proband presented with severe combined immune deficiency (SCID), megaloblastic anemia and neurologic abnormalities. In this study, we examined the impact of MTHFD1 loss‐of‐function on DNA stability. Patient fibroblasts exhibited increased DNA damage relative to control fibroblasts. γH2AX levels, a marker of double‐strand breaks in DNA, were markedly increased in MTHFD1‐deficient patient fibroblasts relative to both control lines as well as the adenosine deaminase deficient fibroblast lines. γH2AX staining increased in patient fibroblasts when cultured in folate‐deficient medium as compared to fibroblasts cultured in folate‐replete medium, indicating that the MTHFD1‐deficient fibroblasts are sensitized to folate deficiency‐induced DNA damage.