ArticleProceedings of the National Academy of Sciences of the United States of America2025
Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Navigating luminal heterogeneity: etiology-based proteogenomic subtyping for targeted treatment strategies in breast cancer.Molecular cancer · 2026Article
- Metabolic isotopic labeling of (deoxy)ribose enables dual neutral loss scanning for profiling nucleic acid modifications.Nucleic acids research · 2026Article
- [Research advances in clonal hematopoiesis associated with hematopoietic stem cell transplantation].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2026Review
- What is in a name? Rethinking SMUG1 in genome maintenance.NAR cancer · 2025Review
- Dynamic genome-wide mapping reveals how chromatin context shapes OGG1-mediated repair and related mutagenesis in human cells.Nucleic acids research · 2025Article
- Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells.Epigenetics & chromatin · 2025Article
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10 authors.
Funding
Abstract
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the mutant TET2 Asn1387Thr (N1387T) in HEK293T cells leads to hmU accumulation, with levels further increased in cells lacking the glycosylase SMUG1. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. N1300T cells accumulate more additional mutations with extended culture and exhibit heightened sensitivity to ATR inhibition compared to
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