Some of the most prevalent mutations in human cancers and genetic diseases are C to T transitions in CpG nucleotides. This has been attributed to the deamination of 5-methylcytosine (5mC), an epigenetic modification found in CpGs, but Marketa Tomkova, previously of the Schuster-Boeckler and Kriaucionis groups and now leading the Tomkova group, and Michael McClellan of the Kriaucionis group have shown that CpG>TpG mutations are frequently introduced as errors during DNA replication by DNA polymerase ε (Pol ε).
The team have developed a new method, Polymerase Error Rate Sequencing (PER-seq), to measure the error spectrum of DNA polymerases in isolation. Using PER-seq, they show that human DNA Pol ε produces an excess of CpG>TpG errors. Interestingly, the wild-type Pol ε was seen to have a 7-fold higher error rate when replicating 5mCpG compared to cytosine in other contexts. This has led to a fundamental change in our understanding of the disease-causing mutational mechanism, as they have demonstrated that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells.
The demonstration that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells has fundamentally changed our understanding of this most prevalent disease-causing mutational pattern.
To find out more, see the full article in Nature Genetics and read a full review from Ludwig Cancer Research.