Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Abstract

Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)-and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As 2 O 3 ), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As 2 O 3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As 2 O 3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As 2 O 3 -induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.MTHFD1 | arsenic trioxide | one-carbon metabolism | SUMO-1

Deoxyuracil in DNA and disease: Genomic signal or managed situation?

“…Folate depletion has been repeatedly shown to lead to apoptosis across several cell culture and mouse models (4). Arsenic trioxide treatment was associated with proteolytic degradation of SHMT1 and MTHFD1, increased uracil incorporation into DNA and increased DNA damage in HeLa cells (86). Arsenic trioxide has also been shown to induce apoptosis in HeLa cells (87).…”

The role of dNTP metabolites in control of the embryonic cell cycle

“…Except for the nuclear SHMT2α, SHMT1 together with dihydrofolate reductase (DHFR) and dTMP synthase (TYMS) are post-translationally modified by the small ubiquitin-like modifier (SUMO) to translocate to the nuclear lamina [65][66][67]. Alternatively, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1, encoded by pugilist in Drosophila) catalyzes THF, ATP, and formate to yield 10-formylTHF and further N5,N10methylentetrahydrofolate (5,10-meTHF) in the cytosol and nucleus [68]. The Drosophila genome contains a single SHMT gene that encodes three transcripts, which are proteolytically derived from a longer precursor with a putative mitochondrial presequence.…”

Folate status in women of reproductive age as basis of neural tube defect risk assessment

“…For example, exposure to low doses of arsenic from contaminated drinking water and food can decrease the efficacy of folic acid in NTD prevention . Nuclear folate–dependent de novo thymidylate biosynthesis has been demonstrated to be a sensitive target of arsenic, providing a mechanism for arsenic in the etiology of developmental anomalies . As nutrition status may explain individual differences in susceptibility to arsenic toxicity, there is a particular need for public health interventions targeting folate and other micronutrient deficiencies in arsenic‐exposed regions …”

“…40 Nuclear folate-dependent de novo thymidylate biosynthesis has been demonstrated to be a sensitive target of arsenic, providing a mechanism for arsenic in the etiology of developmental anomalies. 41 As nutrition status may explain individual differences in susceptibility to arsenic toxicity, there is a particular need for public health interventions targeting folate and other micronutrient deficiencies in arsenic-exposed regions. 42,43 Socioeconomic variables associated with poverty are recognized to influence folate status, 44 such as in Guatemala, where the national prevalence of folate insufficiency among WRA is approximately 50%, but varies considerably by region and socioeconomic characteristics, 45 as discussed below.…”