TY - JOUR
T1 - Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure
AU - McDaniel, Yumeng Z.
AU - Wang, Dake
AU - Love, Robin P.
AU - Adolph, Madison B.
AU - Mohammadzadeh, Nazanin
AU - Chelico, Linda
AU - Mansky, Louis M.
N1 - Publisher Copyright:
© 2020 Oxford University Press. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
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U2 - 10.1093/NAR/GKZ1164
DO - 10.1093/NAR/GKZ1164
M3 - Article
C2 - 31943071
AN - SCOPUS:85082145326
SN - 0305-1048
VL - 48
SP - 1353
EP - 1371
JO - Nucleic acids research
JF - Nucleic acids research
IS - 3
ER -