Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration
Open accessAbstract
We report that the mammalian 5-methylcytosine (5mC) oxidase Tet3 exists as three major isoforms and characterized the full-length isoform containing an N-terminal CXXC domain (Tet3FL). This CXXC domain binds to unmethylated CpGs, but, unexpectedly, its highest affinity is toward 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain-5caC-DNA complex, revealing the structural basis of the binding specificity of this domain as a reader of CcaCG sequences. Mapping of Tet3FL in neuronal cells shows that Tet3FL is localized precisely at the transcription start sites (TSSs) of genes involved in lysosome function, mRNA processing, and key genes of the base excision repair pathway. Therefore, Tet3FL may function as a regulator of 5caC removal by base excision repair. Active removal of accumulating 5mC from the TSSs of genes coding for lysosomal proteins by Tet3FL in postmitotic neurons of the brain may be important for preventing neurodegenerative diseases.
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TET3 can identify and facilitate removal of 5caC by base excision repair to achieve demethylation of gene regulatory regions.
“A recent study showed that TET3 can identify and facilitate removal of 5caC by base excision repair to achieve demethylation of gene regulatory regions (47).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [47]
The Results (DNA binding properties; page not provided) show that Tet3’s CXXC domain recognizes 5caC. The Discussion (page not provided) proposes that Tet3FL may promote expression of base-excision-repair factors, but does not establish that it facilitates 5caC removal or demethylation at gene regulatory regions. The Results also found no effect of Tet3’s CXXC domain on TDG cleavage of 5caC. (LLM, conf=0.88)
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TET2 chemically modifies tRNAs and regulates tRNA fragment levels
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“A recent study showed that TET3 can identify and facilitate removal of 5caC by base excision repair to achieve demethylation of gene-regulatory regions.(47) Thus, future work is needed to examine the entire 5mC oxidation pathway in liver.”
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The role of TET proteins in stress-induced neuroepigenetic and behavioural adaptations
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TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment
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TET-dioxygenase deficiency in oncogenesis and its targeting for tumor-selective therapeutics
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Solving the conundrum of insoluble protein aggregates
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TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis
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A non-catalytic role of TET3 promotes open chromatin and enhances global transcriptionPreprint
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Demethylation in Early Embryonic Development and Memory
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Establishment, Erasure and Synthetic Reprogramming of DNA Methylation in Mammalian Cells
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Reading Time and DNA Sequence Preference of TET3 CXXC Domain Revealed by Single‐Molecule Profiling†
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- Authors
- Jin, S.-G., Zhang, Z.-M., Dunwell, T. L., Harter, M. R., Wu, X., Johnson, J., Li, Z., Liu, J., Szabó, P. E., Lu, Q., Xu, G.-L., Song, J., & Pfeifer, G. P.
- Affiliations
- Van Andel Institute (US)
- Beckman Research Institute (US)
- University of California, Riverside (US)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Song, Jikui
- Pfeifer, Gerd P.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 14
- Issue
- 3
- Pages
- 493-505
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4731272
- OpenAlex
- W2225733508
- Cited by
- 138
- References
- 73
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 6 · 2023: 12 · 2022: 14 · 2021: 12 · 2020: 9 · 2019: 25 · 2018: 21 · 2017: 15 · 2016: 6
- FWCI
- 11.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- NIH (CA160965, GM064378, NS075393, MH094599)
- Sidney Kimmel Foundation for Cancer Research
- University of California Cancer Research Coordination Committee (CRC-15-380558)
- UCR Regent Fellowship
- March of Dimes Foundation (1-FY15-345)
- City of Hope – UC Riverside Biomedical Research Initiative
- Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TET3, 5-carboxylcytosine, CXXC domain, DNA demethylation, 5-methylcytosine oxidation, base excision repair, transcription start sites, lysosomal genes, neurons, neurodegeneration, crystal structure
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Cell Line, Cytosine, DNA Repair, DNA-Binding Proteins, Female, Histones, Humans, Lysosomes, Mice, Inbred C57BL, Molecular Sequence Data, Nucleic Acid Conformation, Proto-Oncogene Proteins, Xenopus, Protein Structure, Tertiary, Crystallography, X-Ray, DNA Methylation, Protein Isoforms, Amino Acid Motifs, Transcription Initiation Site, Dioxygenases, Mice, HEK293 Cells
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