Understanding mutagenesis in somatic cells

Mutations drive phenotypic changes that underlie evolution, genetic disease and carcinogenesis. Understanding how, where and when changes to the DNA sequence occur is therefore important. Experiments that address this most commonly make use of highly proliferative cells, cultured in the lab. However, in relation to carcinogenesis it is of particular importance to understand the process of mutagenesis in somatic cells, which generally undergo no or limited cell divisions. We recently established the mechanism for an indel mutational signature that occurs in cancer and the germline. We showed this to be due to genome-embedded ribonucleotides and the action of topoisomerase 1, an enzyme that relieves topological stress, with mutations of this type more common in genes that are highly expressed, providing a basis for transcription-associated mutagenesis (Reijns, Parry, Williams et al. Nature, 2022).

Since this discovery, it has become clear that this signature also occurs in somatic cells, such as neurons. However, as ribonucleotides are largely thought to be incorporated during DNA replication in S-phase, our ongoing work aims to understand the similarities and differences in the mechanism that cause these mutations in non-dividing cells. Possible projects relating to this will involve a range of cell and molecular biology techniques, including flow cytometry, targeted DNA capture and short/long-read NGS, as well as bioinformatics analyses. Our investigations range from using cultured mammalian or yeast cells that are forced out of cycle to mouse models to study this in neurons and hepatocytes. Ultimately, we aim to understand how the interplay between DNA damage/repair, genome-embedded ribonucleotides and topological stress at highly transcribed genes may cause mutations in somatic cells, with implications for cancer and ageing.