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APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication
Vladimir B Seplyarskiy1, Ruslan A Soldatov2, Konstantin Y Popadin3
1Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia, 127051; Lomonosov Moscow State University, Moscow, Russia, 119991; Pirogov Russian National Research Medical University, Moscow, Russia, 117997;
Abstract:
APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double-stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus unraveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mutation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two. Finally, we show that in cancers with extensive APOBEC-induced mutagenesis, there is almost no increase in mutation rates in late replicating regions (contrary to other cancers). Because late-replicating regions are depleted in exons, this results in a 1.3-fold higher fraction of mutations residing within exons in such cancers. This study provides novel insight into the APOBEC-induced mutagenesis and describes the peculiarity of the mutational processes in cancers with the signature of APOBEC-induced mutations.
Insights
APOBEC enzymes cause mutations in cancer. This study reveals >33% of dispersed mutations occur on the lagging strand during DNA replication, identifying a key source of DNA targeted by APOBEC in cancer.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- APOBEC3A and APOBEC3B are key cytidine deaminases driving mutations in human cancers.
- APOBEC-mediated mutations can occur as clustered events (kataegis) or dispersed mutations.
- The source and genomic distribution of single-stranded DNA (ssDNA) targeted by APOBEC for dispersed mutations remain largely uncharacterized.
Purpose of the Study:
- To identify the major source of ssDNA targeted by APOBEC enzymes for dispersed mutations in cancer.
- To investigate the influence of DNA methylation on APOBEC-induced mutagenesis.
- To analyze the genomic distribution and exonic enrichment of APOBEC-induced mutations in specific cancer types.
Main Methods:
- Analysis of genomic and exomic cancer databases.
- Characterization of mutation patterns, including clustered and dispersed mutations.
- Assessment of mutation rates in relation to DNA replication timing and DNA methylation status.
Main Results:
- >33% of dispersed APOBEC-induced mutations originate from the lagging strand during DNA replication, identifying this as a primary ssDNA target.
- DNA methylation was found to reduce the rate of APOBEC-induced mutations by approximately twofold.
- Cancers with high APOBEC mutagenesis show minimal mutation rate increase in late-replicating regions, leading to a 1.3-fold higher fraction of mutations within exons.
Conclusions:
- DNA replication, specifically the lagging strand, is a major source of ssDNA targeted by APOBEC in cancer.
- DNA methylation has a protective effect against APOBEC-induced mutagenesis.
- APOBEC-driven mutagenesis exhibits distinct patterns in late-replicating regions and leads to increased exonic mutation burden in specific cancers.
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