DNA mutagenesis driven by transcription factor competition with mismatch repair

Despite the remarkable fidelity of eukaryotic DNA replication, nucleotide misincorporation errors occur in every replication cycle, generating mutations that drive genetic diseases and genome evolution. Here, we show that transcription factor (TF) proteins, key players in gene regulation, can increase mutagenesis from replication errors by directly competing with the recognition of DNA mismatches by MutSα, the primary initiator of eukaryotic mismatch repair (MMR). We demonstrate this TF-induced mutagenesis mechanism using a yeast genetic assay that quantifies the accumulation of mutations in TF binding sites. Analyses of human cancer mutations recapitulate the trends observed in yeast, with mutations arising from MYC-bound mismatches being enriched in MMR-proficient cells. These findings implicate TF-MMR competition as a critical determinant of somatic hypermutation at TF binding sites in cancer. Furthermore, our results provide a molecular mechanism for the higher-than-expected rate of rare genetic variants at TF binding sites, with important implications for regulatory DNA evolution.