Similar Datasets
Project description:The distribution of somatic mutations across the genome is not uniform. Recently, an unexpected pattern of hyper-mutation was reported at binding sites of transcriptional regulatory factors (TFs). In some human cells, a decrease in DNA repair activity was also observed at TF binding sites, leading to the hypothesis that TFs may increase mutagenesis by interfering with the recognition of DNA lesions by repair enzymes, and thus inhibiting repair. However, direct proof of this surprising TF-induced mutagenesis mechanism is lacking. Here, we show that TF binding to DNA mismatch lesions leads to increased mutation rates at TF binding sites by reducing the efficiency of lesion recognition by MutSα, the main enzyme that initiates mismatch repair in eukaryotic cells. We developed a yeast mutagenesis assay to directly observe the accumulation of mutations in a TF binding site. Upon TF overexpression, the binding site exhibited an increased mutation rate, specifically for mutations resulting from mismatches where the TF strongly reduced MutSα binding in vitro. This trend was amplified in cells with an increased rate of misincorporation errors, and it was not observed in mismatch repair-deficient cells. Analyses of human cancer somatic mutation data revealed a pattern similar to that observed in yeast, with mutations resulting from TF-bound mismatches being specifically enriched in mismatch repair-proficient tumors. Taken together, our results demonstrate that in addition to their well-known roles in gene regulation, TFs also play a role in DNA mutagenesis, by directly interfering with the repair of replication errors. Since a majority of cancer mutations originate from unrepaired replication errors, most commonly mismatches, our results suggest that TF interference with mismatch repair will shape the mutation landscape of regulatory DNA in cancer genomes.
2025-03-31 | GSE235855 | GEO
Project description:The distribution of somatic mutations across the genome is not uniform. Recently, an unexpected pattern of hyper-mutation was reported at binding sites of transcriptional regulatory factors (TFs). In some human cells, a decrease in DNA repair activity was also observed at TF binding sites, leading to the hypothesis that TFs may increase mutagenesis by interfering with the recognition of DNA lesions by repair enzymes, and thus inhibiting repair. However, direct proof of this surprising TF-induced mutagenesis mechanism is lacking. Here, we show that TF binding to DNA mismatch lesions leads to increased mutation rates at TF binding sites by reducing the efficiency of lesion recognition by MutSα, the main enzyme that initiates mismatch repair in eukaryotic cells. We developed a yeast mutagenesis assay to directly observe the accumulation of mutations in a TF binding site. Upon TF overexpression, the binding site exhibited an increased mutation rate, specifically for mutations resulting from mismatches where the TF strongly reduced MutSα binding in vitro. This trend was amplified in cells with an increased rate of misincorporation errors, and it was not observed in mismatch repair-deficient cells. Analyses of human cancer somatic mutation data revealed a pattern similar to that observed in yeast, with mutations resulting from TF-bound mismatches being specifically enriched in mismatch repair-proficient tumors. Taken together, our results demonstrate that in addition to their well-known roles in gene regulation, TFs also play a role in DNA mutagenesis, by directly interfering with the repair of replication errors. Since a majority of cancer mutations originate from unrepaired replication errors, most commonly mismatches, our results suggest that TF interference with mismatch repair will shape the mutation landscape of regulatory DNA in cancer genomes.
2025-03-31 | GSE235854 | GEO
Project description:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987708 | ENA
Project description:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987713 | ENA
Project description:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987711 | ENA
Project description:Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.
| S-EPMC3341054 | biostudies-literature
Project description:The mutation rate of an organism is influenced by the interaction of evolutionary forces such as natural selection and genetic drift. However, the mutation spectrum (i.e., the frequency distribution of different types of mutations) can be heavily influenced by DNA repair. Using mutation-accumulation lines of the extremophile bacterium Deinococcus radiodurans ΔmutS1 and the model soil bacterium Pseudomonas fluorescens wild-type and MMR- (Methyl-dependent Mismatch Repair-deficient) strains, we report the mutational features of these two important bacteria. We find that P. fluorescens has one of the highest MMR repair efficiencies among tested bacteria. We also discover that MMR of D. radiodurans preferentially repairs deletions, contrary to all other bacteria examined. We then, for the first time, quantify genome-wide efficiency and specificity of MMR in repairing different genomic regions and mutation types, by evaluating the P. fluorescens and D. radiodurans mutation data sets, along with previously reported ones of Bacillus subtilis subsp. subtilis, Escherichia coli, Vibrio cholerae, and V. fischeri. MMR in all six bacteria shares two general features: 1) repair efficiency is influenced by the neighboring base composition for both transitions and transversions, not limited to transversions as previously reported; and 2) MMR only recognizes indels <4 bp in length. This study demonstrates the power of mutation accumulation lines in quantifying DNA repair and mutagenesis patterns.
| S-EPMC6188547 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-22 | GSE98608 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2012-12-01 | E-GEOD-41617 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-22 | GSE150530 | GEO