title: APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication.
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.
authors.affiliation: Institute 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;
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Seplyarskiy
authors.affiliation: Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia, 127051; Lomonosov Moscow State University, Moscow, Russia, 119991;
authors.forename: Ruslan A
authors.initials: RA
authors.lastname: Soldatov
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland;
authors.forename: Konstantin Y
authors.initials: KY
authors.lastname: Popadin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland;
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Institute 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;
authors.forename: Georgii A
authors.initials: GA
authors.lastname: Bazykin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
mesh_terms: D003564:Cytidine Deaminase / Q000502:physiology*; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004261:DNA Replication; D059472:Exome; D006801:Humans; D016296:Mutagenesis; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*
chemical_list: D003596:Cytosine; D003564:Cytidine Deaminase