en
Scientific article
Open access
English

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

Published inGenome research, vol. 26, no. 2, p. 174-182
Publication date2016
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/physiology
  • Cytosine/metabolism
  • DNA Methylation
  • DNA Mutational Analysis
  • DNA Replication
  • Exome
  • Humans
  • Mutagenesis
  • Mutation
  • Mutation Rate
  • Neoplasms/genetics
Citation (ISO format)
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
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal1088-9051
489views
195downloads

Technical informations

Creation11/16/2016 9:50:00 AM
First validation11/16/2016 9:50:00 AM
Update time03/15/2023 12:56:20 AM
Status update03/15/2023 12:56:20 AM
Last indexation01/16/2024 10:16:43 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack