ArticleNature genetics2024
Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.
Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- The rate and spectrum of germline mutations in chicken from a commercial pedigree line.Genetics, selection, evolution : GSE · 2026Article
- APOBEC3 activity and DNA polymerase-ε deficiency are associated with distinct IDH1 R132 hotspot mutations.Molecular oncology · 2026Article
- Review
- Identification and validation of a previously missed mutational signature in colorectal cancer.Nature communications · 2026Article
- Human PMS1-dependent non-canonical mismatch repair engages with MBD4 to repair methylated CpG deamination.Nucleic acids research · 2026Article
- Article
- Genomic distribution characteristics and interspecific differences of microsatellite landscapes in Felidae.BMC genomics · 2026Article
- Single-cell whole-genome sequencing reveals convergent evolution in Burkitt lymphoma.Nature communications · 2026Article
- Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.PLoS genetics · 2026Article
- Molecular Characterization ofCancers · 2026Article
- Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.bioRxiv : the preprint server for biology · 2026Article
- Mutational signature-based classification uncovers emerging oral cancer subtypes with distinct molecular patterns.International journal of oral science · 2026Article
- Topographical archetypes of somatic mutagenesis in cancer.bioRxiv : the preprint server for biology · 2026Article
- Detection of a sequence feature for recursive splicing.bioRxiv : the preprint server for biology · 2026Article
- Somatic mutations and clonal evolution in normal tissues and cancer development.Experimental & molecular medicine · 2026Review
- Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.Nature genetics · 2026Article
- Interpreting cancer genetics through a two-step "evolutionary cascade hypothesis": bridging neutral and selective perspectives.Journal of translational medicine · 2026Review
- Mbd4 and MutSα protect cells from spontaneous deamination of 5-methylcytosine.Nucleic acids research · 2026Article
- Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.Nature genetics · 2026Article
- Broadening the inheritedGenetics in medicine open · 2026Article
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Authors and funding
10 authors.
Funding
Abstract
C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism.
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