A Spontaneous Ring-Opening Reaction Leads to a Repair-Resistant Thymine Oxidation Product in Genomic DNA.
Chembiochem : a European journal of chemical biology
John Wiley & Sons Ltd.
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Sahakyan, A., Mahtey, A., Kawasaki, F., & Balasubramanian, S. (2020). A Spontaneous Ring-Opening Reaction Leads to a Repair-Resistant Thymine Oxidation Product in Genomic DNA.. Chembiochem : a European journal of chemical biology, 21 (3), 320-323. https://doi.org/10.1002/cbic.201900484
The alphabet of modified DNA bases goes beyond the conventional four letters, with biological roles being found for many such modifications. Here we describe a novel observation for the thymine base that arises via spontaneous N1-C2 ring opening of its oxidation product 5-formyl uracil, after N3-deprotonation. We first observed this phenomenon in silico though ab initio calculations, followed by in vitro experiments to verify its formation at a mononucleoside level and in a synthetic DNA oligonucleotide context. We show that the new base modification (Trex, Thymine ring expunged) can form under physiological conditions, and is resistant to the action of common repair machineries. Furthermore, we found cases of natural existence of Trex in vivo, while screening a number of human cell types and mESC (E14), suggesting potential biological relevance of this modification.
The University of Cambridge, Vice Chancellor’s Award (Cambridge Trust) and the Dudding & Stachulski Scholarship
Wellcome Trust (209441/Z/17/Z)
Cancer Research UK (CB4330)
Cancer Research UK (18618)
External DOI: https://doi.org/10.1002/cbic.201900484
This record's URL: https://www.repository.cam.ac.uk/handle/1810/295533
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