Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1071536 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27799012_1.fastq.gz | Fastqsanger.gz | |||
| SRR27799012_2.fastq.gz | Fastqsanger.gz | |||
| SRR27799013_1.fastq.gz | Fastqsanger.gz | |||
| SRR27799013_2.fastq.gz | Fastqsanger.gz | |||
| SRR27799014_1.fastq.gz | Fastqsanger.gz |
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Project description:Mouse models of mismatch repair deficiency
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Project description:The sources of genome instability, a hallmark of cancer, remain incompletely understood. One potential source is DNA re-replication, which arises when the mechanisms that prevent re-initiation of replication origins within a single cell cycle are compromised. Using the budding yeast Saccharomyces cerevisiae, we previously showed that DNA re-replication is extremely potent at inducing gross chromosomal alterations and that this arises in part because of the susceptibility of re-replication forks to break. Here, we examine the ability of DNA re-replication to induce nucleotide level mutations. During normal replication these mutations are restricted by three overlapping error avoidance mechanisms: the nucleotide selectivity of replicative polymerases, their proofreading activity, and mismatch repair. Using lys2InsEA14, a frameshift reporter that is poorly proofread, we show that re-replication induces up to a 30x higher rate of frameshift mutations and that this mutagenesis is due to passage of the re-replication fork, not secondary to re-replication fork breakage. Re-replication can also induce comparable rates of frameshift and base substitution mutations in a more general mutagenesis reporter CAN1, when the proofreading activity of DNA polymerase ε is inactivated. Finally, we show that the induction of lys2InsEA14 frameshift mutations by re-replication is dependent on mismatch repair. These results suggest that the mismatch repair associated with re-replication is attenuated, although at most sequences DNA polymerase proofreading provides enough error correction to mitigate the mutagenic consequences. Thus, re-replication can facilitate nucleotide level mutagenesis in addition to inducing gross chromosomal alterations, broadening its potential role in genome instability.
2018-12-27 | GSE124382 | 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: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:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987708 | ENA
Project description:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987711 | ENA
Project description:DNA mutagenesis driven by transcription factor competition with mismatch repair
| PRJNA987713 | ENA
Project description:This study examined the expression profile of medullary carcioma of the colon compared to adjacent histologically normal colonic mucosa. Medullary carcinomas of the colon were selected from Rhode Island Hosptial and The Miriam Hospital to identify new molecular markers of this disease. Medullary carcinoma was defined by applying strict morphologic criteria and demonstration of mismatch repair protein deficiency (MMRd) by IHC.
2016-04-01 | E-GEOD-76855 | biostudies-arrayexpress