Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

The Kriaucionis, Schuster-Boeckler and Tomkova groups show that DNA polymerase ε makes errors when replicating methylated CpGs, producing C>T mutations at CpG dinucleotides.

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.