Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure

Yumeng Z. McDaniel, Dake Wang, Robin P. Love, Madison B. Adolph, Nazanin Mohammadzadeh, Linda Chelico, Louis M. Mansky

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3, A3) family member proteins can deaminate cytosines in singlestrand (ss) DNA, which restricts human immunodeficiency virus type 1 (HIV-1), retrotransposons, and other viruses such as hepatitis B virus, but can cause a mutator phenotype in many cancers. While structural information exists for several A3 proteins, the precise details regarding deamination target selection are not fully understood. Here, we report the first parallel, comparative analysis of site selection of A3 deamination using six of the seven purified A3 member enzymes, oligonucleotides having 5_TC3_ or 5_CT3_ dinucleotide target sites, and different flanking bases within diverse DNA secondary structures. A3A, A3F and A3H were observed to have strong preferences toward the TC target flanked by A or T, while all examined A3 proteins did not show a preference for a TC target flanked by a G. We observed that the TC targetwas strongly preferred in ssDNA regions rather than dsDNA, loop or bulge regions, with flanking bases influencing the degree of preference. CT was also shown to be a potential deamination target. Taken together, our observations provide new insights into A3 enzyme target site selection and how A3 mutagenesis impacts mutation rates.

Original languageEnglish (US)
Pages (from-to)1353-1371
Number of pages19
JournalNucleic acids research
Volume48
Issue number3
DOIs
StatePublished - 2020

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