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

Gabriel J. Starrett, Elizabeth M. Luengas, Jennifer L. McCann, Diako Ebrahimi, Nuri A. Temiz, Robin P. Love, Yuqing Feng, Madison B. Adolph, Linda Chelico, Emily K. Law, Michael A. Carpenter and Reuben S Harris ()
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Gabriel J. Starrett: Molecular Biology and Biophysics, University of Minnesota
Elizabeth M. Luengas: Molecular Biology and Biophysics, University of Minnesota
Jennifer L. McCann: Molecular Biology and Biophysics, University of Minnesota
Diako Ebrahimi: Molecular Biology and Biophysics, University of Minnesota
Nuri A. Temiz: Molecular Biology and Biophysics, University of Minnesota
Robin P. Love: University of Saskatchewan
Yuqing Feng: University of Saskatchewan
Madison B. Adolph: University of Saskatchewan
Linda Chelico: University of Saskatchewan
Emily K. Law: Molecular Biology and Biophysics, University of Minnesota
Michael A. Carpenter: Molecular Biology and Biophysics, University of Minnesota
Reuben S Harris: Molecular Biology and Biophysics, University of Minnesota

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12918

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