A Spontaneous Ring‐Opening Reaction Leads to a Repair‐Resistant Thymine Oxidation Product in Genomic DNA
Author(s) -
Sahakyan Aleksandr B.,
Mahtey Areeb,
Kawasaki Fumiko,
Balasubramanian Shankar
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900484
Subject(s) - thymine , oligonucleotide , dna , deprotonation , context (archaeology) , chemistry , uracil , ring (chemistry) , in silico , nucleobase , stereochemistry , combinatorial chemistry , biology , biochemistry , gene , organic chemistry , ion , paleontology
Abstract The alphabet of modified DNA bases goes beyond the conventional four letters, with biological roles being found for many such modifications. Herein, we describe the observation of a modified thymine base that arises from spontaneous N 1 −C 2 ring opening of the oxidation product 5‐formyl uracil, after N 3 deprotonation. We first observed this phenomenon in silico through 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 (T rex , t hymine r ing ex punged) can form under physiological conditions, and is resistant to the action of common repair machineries. Furthermore, we found cases of the natural existence of T rex while screening a number of human cell types and mESC (E14), thus suggesting potential biological relevance of this modification.