Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli
- PMID: 26839411
- PMCID: PMC4776466
- DOI: 10.1073/pnas.1522325113
Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli
Abstract
The rate of cytosine deamination is much higher in single-stranded DNA (ssDNA) than in double-stranded DNA, and copying the resulting uracils causes C to T mutations. To study this phenomenon, the catalytic domain of APOBEC3G (A3G-CTD), an ssDNA-specific cytosine deaminase, was expressed in an Escherichia coli strain defective in uracil repair (ung mutant), and the mutations that accumulated over thousands of generations were determined by whole-genome sequencing. C:G to T:A transitions dominated, with significantly more cytosines mutated to thymine in the lagging-strand template (LGST) than in the leading-strand template (LDST). This strand bias was present in both repair-defective and repair-proficient cells and was strongest and highly significant in cells expressing A3G-CTD. These results show that the LGST is accessible to cellular cytosine deaminating agents, explains the well-known GC skew in microbial genomes, and suggests the APOBEC3 family of mutators may target the LGST in the human genome.
Keywords: APOBEC3A; APOBEC3B; cancer genome mutations; kataegis; uracil-DNA glycosylase.
Conflict of interest statement
The authors declare no conflict of interest.
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