Differential ETS1 Binding to T:G Mismatches Within a CpG Dinucleotide Contributes to C-to-T Somatic Mutation Rate of the IDH2 Hotspot at Codon Arg140

Authors

Jie Yang
Esha Gupta
John R Horton
Robert M Blumenthal
Xing Zhang
Xiaodong Cheng

Publication Date

5-1-2022

Journal

DNA Repair

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.

Keywords

Endodeoxyribonucleases, Thymine, Mutation Rate, DNA, Cytosine, Codon, DNA Repair, ETS1, 5-methylcytosine, 5mC deamination, T:G mismatch, MBD4, IDH2 hotspot mutation, CpG dinucleotide

DOI

10.1016/j.dnarep.2022.103306

PMID

35255310

PMCID

PMC9411267

PubMedCentral® Posted Date

8-26-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes