近日，美国杜克大学教授Raluca Gordan及其团队的最新研究探明了转录因子竞争与错配修复驱动的DNA突变。这一研究成果于2025年7月29日发表在国际顶尖学术期刊《细胞》上。

研究组发现转录因子（TF）蛋白是基因调控的关键角色，可以通过与真核错配修复（MMR）的主要启动者MutSα对DNA错配的识别直接竞争来增加复制错误的突变。研究人员通过酵母遗传分析证明了这种TF诱导的诱变机制，该分析量化了TF结合位点突变的积累。对人类癌症突变的分析概括了在酵母中观察到的趋势，由MYC结合错配引起的突变在MMR精通的细胞中富集。这些发现暗示TF-MMR竞争是肿瘤中TF结合位点体细胞超突变的关键决定因素。

此外，他们的研究结果为TF结合位点的罕见遗传变异率高于预期提供了分子机制，对调控DNA进化具有重要意义。

据悉，尽管真核生物DNA复制具有非凡的保真度，但核苷酸错误合并错误在每个复制周期中都会发生，从而产生驱动遗传疾病和基因组进化的突变。

附：英文原文

Title: DNA mutagenesis driven by transcription factor competition with mismatch repair

Author: Wei Zhu, Yuning Zhang, Harshit Sahay, Hana Wasserman, Ariel Afek, Jonathan Williams, Samantha Shaltz, Caitlin Johnson, Kyle Pinheiro, David M. MacAlpine, Keith R. Weninger, Dorothy A. Erie, Sue Jinks-Robertson, Raluca Gordan

Issue&Volume: 2025-07-29

Abstract: 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.

DOI: 10.1016/j.cell.2025.07.003

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00792-5