Methionine synthase is essential for cancer cell proliferation in physiological folate environments
Sullivan, M. R.; Darnell, A. M.; Reilly, M. F.; Lewis, C. A.; Vander Heiden, M. G.
Show abstract
Targeting folate metabolism can be an effective way to treat cancer. The enzyme methionine synthase catalyzes a key reaction in both folate and methionine metabolism. Early work suggested that inhibiting methionine synthase might restrain tumor growth, though the mechanism remains unclear. We find that due to its specific role in processing folates, methionine synthase is required for cancer proliferation. However, widely used cell culture conditions obscure the proliferative and metabolic consequences of methionine synthase inhibition. Complete dependence on methionine synthase only arises when 5-methyl tetrahydrofolate, the major folate found in circulation, is the predominant folate source provided to cells. In these physiological folate conditions, methionine synthase activity is necessary to maintain intracellular levels of nucleotides, but not methionine. These data reveal that the extracellular environment can alter the essentiality of methionine synthase and suggest that this enzyme plays a crucial cell-autonomous role in supporting nucleotide synthesis and cell proliferation in physiological contexts.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis 94%
- FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells 94%
- Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling 93%
Similar papers in this journal
- PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma 95%
- EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes 93%
- CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis 93%
Similar papers in this journal
- CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors. 94%
- Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1 93%
- CHAMP1 Complex Promotes Heterochromatin Assembly and Reduces Replication Stress 92%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.