ArticleeLife2018
Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair.
Article in eLife, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- Replication stress in cancer: origins, consequences and therapeutic opportunities.Nature reviews. Cancer · 2026Review
- Article
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- Endogenous Metabolites and Genome Instability in Aging and Disease.Chemical research in toxicology · 2023Review
- Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules.Cell chemical biology · 2023Article
- Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.Molecular genetics and genomics : MGG · 2023Article
- Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.BMC genomics · 2023Article
- Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing.bioRxiv : the preprint server for biology · 2023Article
- Article
- Review
- Probing altered enzyme activity in the biochemical characterization of cancer.Bioscience reports · 2022Review
- Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair.Cells · 2021Review
- The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals.International journal of molecular sciences · 2021Review
- Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles.Communications biology · 2021Article
- Cancers from NovelCancer research · 2020Article
- Article
- A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response.JCI insight · 2020Article
- POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status.Molecular cell · 2020Article
- High mutational burden in colorectal carcinomas with monoallelic POLE mutations: absence of allelic loss and gene promoter methylation.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2020Article
- Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance.Science signaling · 2020Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.