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

Genome Res 2016 Feb 11;26(2):174-82. Epub 2016 Jan 11.

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.

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.

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Source
http://dx.doi.org/10.1101/gr.197046.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728370PMC
February 2016
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