APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication
- Vladimir B. Seplyarskiy1,2,3,
- Ruslan A. Soldatov1,2,
- Konstantin Y. Popadin4,5,
- Stylianos E. Antonarakis4,5,
- Georgii A. Bazykin1,2,3 and
- Sergey I. Nikolaev4,5,6
- 1Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia, 127051;
- 2Lomonosov Moscow State University, Moscow, Russia, 119991;
- 3Pirogov Russian National Research Medical University, Moscow, Russia, 117997;
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland;
- 5Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland;
- 6Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva, Switzerland
- Corresponding authors: alicodendrochit{at}gmail.com, Sergey.Nikolaev{at}unige.ch
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.197046.115.
- Received July 16, 2015.
- Accepted December 10, 2015.
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