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Updated: Feb 5, 2026
Strand-Specific Analysis of Proteins at Replicating DNA Strands by Enrichment and Sequencing of Protein-Associated Nascent DNA Method
Published on: May 2, 2025
Mutational signature distribution varies with DNA replication timing and strand asymmetry
Marketa Tomkova1, Jakub Tomek2, Skirmantas Kriaucionis1
1Ludwig Cancer Research Oxford, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Background:
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 strand asymmetry of mutational signatures around replication origins and between early and late replicating regions.
Results:
We 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.
Conclusions:
Together, our results indicate an interaction between DNA replication, the associated damage repair, and most mutagenic processes.
Insights
DNA replication influences cancer mutations. This study reveals how DNA replication timing and direction correlate with various mutagenic processes, impacting cancer development and repair mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- DNA replication is crucial for mutagenesis.
- The interplay between DNA replication and other mutagenic processes is not well understood.
Purpose of the Study:
- To investigate the relationship between DNA replication and mutagenic processes.
- To quantify strand asymmetry of mutational signatures around replication origins and in early/late replicating regions.
Main Methods:
- Analysis of somatic mutation signatures from 3056 patients across 19 cancer types.
- Quantification of mutational signature strand asymmetry relative to DNA replication timing and direction.
Main Results:
- Most identified mutational signatures show significant correlation with DNA replication timing or direction.
- Distinct associations between signatures and replication provide insights into mutagenic processes.
- Oxidative damage to the nucleotide pool may significantly contribute to esophageal adenocarcinoma mutations.
Conclusions:
- DNA replication interacts with DNA damage repair and most mutagenic processes.
- Understanding these interactions is key to deciphering the mutational landscape of cancer.
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