2024/10/10 by Markéta Tomková, Michael John McClellan, Gilles Crevel +7 · 1 voice · 2 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer Genomics and Diagnostics #Epigenetics and DNA Methylation #Genetic factors in colorectal cancer
paper · doi:10.1038/s41588-024-01945-x
openalex publication_date 2024/10/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.