title: MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability.
abstract: Disruptions in folate-mediated one-carbon metabolism (FOCM) are associated with risk for several pathologies including developmental anomalies such as neural tube defects and congenital heart defects, diseases of aging including cognitive decline, neurodegeneration and epithelial cancers, and hematopoietic disorders including megaloblastic anemia. However, the causal pathways and mechanisms that underlie these pathologies remain unresolved. Because folate-dependent anabolic pathways are tightly interconnected and best described as a metabolic network, the identification of causal pathways and associated mechanisms of pathophysiology remains a major challenge in identifying the contribution of individual pathways to disease phenotypes. Investigations of genetic mouse models and human inborn errors of metabolism enable a more precise dissection of the pathways that constitute the FOCM network and enable elucidation of causal pathways associated with NTDs. In this overview, we summarize recent evidence that the enzyme MTHFD1 plays an essential role in FOCM in humans and in mice, and that it determines the partitioning of folate-activated one carbon units between the folate-dependent de novo thymidylate and homocysteine remethylation pathways through its regulated nuclear localization. We demonstrate that impairments in MTHFD1 activity compromise both homocysteine remethylation and de novo thymidylate biosynthesis, and provide evidence that MTHFD1-associated disruptions in de novo thymidylate biosynthesis lead to genome instability that may underlie folate-associated immunodeficiency and birth defects.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Martha S
authors: MS
authors: Field
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Elena
authors: E
authors: Kamynina
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address: pjs13@cornell.edu.
authors: Patrick J
authors: PJ
authors: Stover
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000201:enzymology / Q000235:genetics; D005492:Folic Acid / Q000096:biosynthesis / Q000235:genetics; D042822:Genomic Instability; D006710:Homocysteine / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D013938:Thymidine Monophosphate / Q000096:biosynthesis*
chemical_list: D015778:Minor Histocompatibility Antigens; D006710:Homocysteine; D013938:Thymidine Monophosphate; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)
keywords: DHFR; DNA replication; Folate; Lamin; MTHFD1; Multi-enzyme complex; SHMT; TYMS; Thymidylate