Abstract
DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. Here, we use somatic mutation signatures – each representing a mutagenic process – derived from 3056 patients spanning 19 cancer types to quantify the asymmetry of mutational signatures around replication origins and between early and late replicating regions. We observe that 22 out of 29 mutational signatures are significantly impacted by DNA replication. The distinct associations of different signatures with replication timing and direction around origins shed new light on several mutagenic processes, for example suggesting that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma. Together, our results indicate an involvement of DNA replication and associated damage repair in most mutagenic processes.
Significance Statement Mutations in the genomes of adult cells can trigger cancer and contribute to aging. Mutations can arise randomly as a result of errors made during the copying of DNA when cells divide. At the same time, the likelihood of different types of mutations varies between tissue types and individuals and depends on environmental mutagens as well as on cellular characteristics. Here, we show that the DNA replication modulates the effects of other mutagenic mechanisms, including for example tobacco smoke and UV light. This ubiquitous influence of DNA replication on mutagenesis might explain why tissues with higher replication rate exhibit increased cancer risk. It also suggests that replication-associated DNA repair mechanisms have a bigger influence on mutagenesis than previously appreciated.
CLASSIFICATION Biological Sciences: Genetics