Abstract
BackgroundDNA 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 strand asymmetry of mutational signatures around replication origins and between early and late replicating regions.ResultsWe observe that most of the detected mutational signatures are significantly correlated with the timing or direction of DNA replication. The properties of these associations are distinct for different signatures and shed new light on several mutagenic processes. For example, our results suggest that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma.ConclusionsTogether, our results indicate an interaction between DNA replication, the associated damage repair, and most mutagenic processes.
Highlights
DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes
Replication bias of mutational signatures DNA replication in eukaryotic cells is initiated around replication origins (ORI), from where it proceeds in both directions, synthesizing the leading strand continuously and the lagging strand discontinuously (Fig. 1a)
Samples with microsatellite instability (MSI) and POLE mutations were treated as separate groups, since they are associated with specific mutational processes
Summary
DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. We use somatic mutation signatures—each representing a mutagenic process—derived from 3056 patients spanning 19 cancer types to quantify the strand asymmetry of mutational signatures around replication origins and between early and late replicating regions. Previous analyses have focused either on the genome-wide distribution of mutation rate or on the strand specificity of individual base changes. These studies revealed that the average mutation frequency is increased in late-replicating regions [6, 7], and that the asymmetric synthesis of DNA during replication leads to strand-specific frequencies of base changes [8,9,10,11]. The extent to which DNA replication influences distinct mutational mechanisms, with their manifold possible causes, remains incompletely understood
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