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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Article number103306
JournalDNA Repair
Volume113
DOIs
StatePublished - 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

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