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Reversal of DNA alkylation damage by two human dioxygenases
Open accessAbstract
The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the DNA lesions 1-methyladenine and 3-methylcytosine, which are generated in single-stranded stretches of DNA. AlkB is an α-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde. Here, we identify two human AlkB homologs, ABH2 and ABH3, by sequence and fold similarity, functional assays, and complementation of the E. coli alkB mutant phenotype. The levels of their mRNAs do not appear to correlate with cell proliferation but tissue distributions are different. Both enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an α-ketoglutarate-dependent reaction, and act by direct damage reversal with the regeneration of the unsubstituted bases. AlkB, ABH2, and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde.
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Cited by
ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility
Zheng, G., Dahl, J. A., Niu, Y., Fedorcsak, P., Huang, C.-M., Li, C. J., Vågbø, C. B., Shi, Y., Wang, W.-L., Song, S.-H., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.015 · Cited by 3,550
“…family of nonheme Fe(II)/ a-ketoglutarate (a-KG)-dependent dioxygenases, which catalyze a wide range of biological oxidations (Dango et al., 2011; Duncan et al., 2002; Falnes et al., 2002; Fu et al., 2010; Gerken et al., 2007; Sedgwick, 2004; Trewick et al., 2002; van den 2 Molecular Cell 49,…”
DNA repair pathways as targets for cancer therapy
Helleday, T., Petermann, E., Lundin, C., Hodgson, B., & Sharma, R. A. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2342 · Cited by 1,666
Role of RNA modifications in cancer
Barbieri, I., & Kouzarides, T. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-020-0253-2 · Cited by 1,312
Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes
Hausinger, R. P. (2004) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230490440541 · Cited by 937
Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells
Barnes, D. E., & Lindahl, T. (2004) · Annual Review of Genetics · doi:10.1146/annurev.genet.38.072902.092448 · Cited by 753
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Metadata
- Authors
- Duncan, T., Trewick, S. C., Koivisto, P., Bates, P. A., Lindahl, T., & Sedgwick, B.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2002-12-16
- Volume
- 99
- Issue
- 26
- Pages
- 16660-16665
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1986849535
- Cited by
- 413
- References
- 0
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- green
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- Duncan, T., Trewick, S. C., Koivisto, P., Bates, P. A., Lindahl, T., & Sedgwick, B. (2002). Reversal of DNA alkylation damage by two human dioxygenases. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.262589799
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