The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis

Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B -null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B -null tumours wi...

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Published in:Nature communications 2016-09, Vol.7 (1), p.12918-13, Article 12918
Main Authors: Starrett, Gabriel J., Luengas, Elizabeth M., McCann, Jennifer L., Ebrahimi, Diako, Temiz, Nuri A., Love, Robin P., Feng, Yuqing, Adolph, Madison B., Chelico, Linda, Law, Emily K., Carpenter, Michael A., Harris, Reuben S
Format: Article
Language:English
Subjects:
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Adenocarcinoma - genetics
Adenocarcinoma - metabolism
Aminohydrolases - genetics
Aminohydrolases - metabolism
Breast Neoplasms - genetics
DNA - genetics
Female
Genetic Predisposition to Disease
Haplotypes
Humanities and Social Sciences
Humans
Lung cancer
Lung Neoplasms - genetics
multidisciplinary
Mutation
Science
Science (multidisciplinary)
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Summary:Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B -null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B -null tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature’ mutations in cancer. The APOBEC family of enzymes are cytidine deaminases with APOBEC3A and APOBEC3B thought to contribute to DNA damage signatures detected in cancer genomes. Here, the authors demonstrate an unappreciated role for APOBEC3H haplotype I in the generation of DNA damage in breast cancer.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms12918