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.

Keywords: DHFR; DNA replication; Folate; Lamin; MTHFD1; Multi-enzyme complex; SHMT; TYMS; Thymidylate.

Figure 1

Folate-Mediated One-Carbon Metabolism. One-carbon metabolism is required for the de novo synthesis of purines and thymidylate, and for the remethylation of homocysteine to methionine. The de novo thymidylate pathway is SUMOylated and translocates to the nucleus during S-phase. Mitochondria generate formate from the amino acids serine and glycine. THF, tetrahydrofolate; AdoMet, S-adenosylmethionine; MTHFD, Methylenetetrahydrofolate Dehydrogenase; MTR, Methionine Synthase; MTHFR, Methylenetetrahydrofolate Reductase; SHMT1, Cytoplasmic Serine Hydroxymethyltransferase; SHMT2α, Serine Hydroxymethyltransferase 2α TYMS, Thymidylate Synthase; DHFR, Dihydrofolate Reductase; GSC, Glycine Cleavage System.

Figure 2

The de novo thymidylate synthesis pathway as a nuclear multienzyme complex at sites of DNA replication. THF, tetrahydrofolate; DHF, dihydrofolate; MTHFD1, Methylenetetrahydrofolate Dehydrogenase; SHMT1, Cytoplasmic Serine Hydroxymethyltransferase; TYMS, Thymidylate Synthase; DHFR, Dihydrofolate Reductase; dUMP, deoxyuridine monophosphate; dUTP, deoxyuridine triphosphate; dTMP, thymidine monophosphate; dTTP, thymidine triphosphate.