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APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication

Seplyarskiy, Vladimir B
Soldatov, Ruslan A
Bazykin, Georgii A
Published in Genome research. 2016, vol. 26, no. 2, p. 174-182
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.
Keywords Cytidine Deaminase/physiologyCytosine/metabolismDNA MethylationDNA Mutational AnalysisDNA ReplicationExomeHumansMutagenesisMutationMutation RateNeoplasms/genetics
PMID: 26755635
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Research group Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
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SEPLYARSKIY, Vladimir B et al. APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. In: Genome research, 2016, vol. 26, n° 2, p. 174-182. doi: 10.1101/gr.197046.115 https://archive-ouverte.unige.ch/unige:89001

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Deposited on : 2016-11-16

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