Analysis of APOBEC-induced mutations in yeast strains with low levels of replicative DNA polymerases
Open Access
- 10 April 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (17), 9440-9450
- https://doi.org/10.1073/pnas.1922472117
Abstract
Yeast strains with low levels of the replicative DNA polymerases (alpha, delta, and epsilon) have high levels of chromosome deletions, duplications, and translocations. By examining the patterns of mutations induced in strains with low levels of DNA polymerase by the human protein APOBEC3B (a protein that deaminates cytosine in single-stranded DNA), we show dramatically elevated amounts of single-stranded DNA relative to a wild-type strain. During DNA replication, one strand (defined as the leading strand) is replicated processively by DNA polymerase epsilon and the other (the lagging strand) is replicated as short fragments initiated by DNA polymerase alpha and extended by DNA polymerase delta. In the low DNA polymerase alpha and delta strains, the APOBEC-induced mutations are concentrated on the lagging-strand template, whereas in the low DNA polymerase epsilon strain, mutations occur on the leading- and lagging-strand templates with similar frequencies. In addition, for most genes, the transcribed strand is mutagenized more frequently than the nontranscribed strand. Lastly, some of the APOBEC-induced clusters in strains with low levels of DNA polymerase alpha or delta are greater than 10 kb in length.Funding Information
- HHS | National Institutes of Health (R35GM118020)
- Department of the Army, Army Research Office (W911NF1920082)
- National Natural Science Foundation of China (31800055)
- National Natural Science Foundation of China (31401058)
- Zhoushan City-Zhejiang University Joint Specific Project (2019C81055)
- US National Institute of Health Intramural Research Program Project (Z1AES103266)
This publication has 49 references indexed in Scilit:
- An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancersNature Genetics, 2013
- A unique nucleosome arrangement, maintained actively by chromatin remodelers facilitates transcription of yeast tRNA genesBMC Genomics, 2013
- DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegiseLife, 2013
- High-Resolution Mapping of Spontaneous Mitotic Recombination Hotspots on the 1.1 Mb Arm of Yeast Chromosome IVPLoS Genetics, 2013
- AID/APOBEC cytosine deaminase induces genome-wide kataegisBiology Direct, 2012
- Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA RegionsMolecular Cell, 2012
- Intrinsic coupling of lagging-strand synthesis to chromatin assemblyNature, 2012
- Division of Labor at the Eukaryotic Replication ForkMolecular Cell, 2008
- Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complexProceedings of the National Academy of Sciences of the United States of America, 2007
- APOBEC3G DNA deaminase acts processively 3′ → 5′ on single-stranded DNANature Structural & Molecular Biology, 2006