Abstract
Cytosine to thymine (C>T) somatic mutation is highly enriched in certain types of cancer, and most commonly occurs via deamination of a 5-methylcytosine (5mC) to thymine, in the context of a CpG dinucleotide. In theory, deamination should occur at equal rates to both 5mC nucleotides on opposite strands. In most cases, the resulting T:G or G:T mismatch can be repaired by thymine DNA glycosylase activities. However, while some hotspot-associated CpG mutations have approximately equal numbers of mutations that resulted either from C>T or G>A in a CpG dinucleotide, many showed strand bias, being skewed toward C>T of the first base pair or G>A of the second base pair. Using the IDH2 Arg140 codon as a case study, we show that the two possible T:G mismatches at the codon-specific CpG site have differing effects on transcription factor ETS1 binding affinity, differentially affecting access of a repair enzyme (MBD4) to the deamination-caused T:G mismatch. Our study thus provides a plausible mechanism for exclusion of repair enzymes by the differential binding of transcription factors affecting the rate at which the antecedent opposite-strand mutations occur.
Original language | English (US) |
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Article number | 103306 |
Journal | DNA Repair |
Volume | 113 |
DOIs | |
State | Published - May 2022 |
Keywords
- 5-methylcytosine
- 5mC deamination
- CpG dinucleotide
- ETS1
- IDH2 hotspot mutation
- MBD4
- T:G mismatch
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology