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, Reuben S. Harris

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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.

Original languageEnglish (US)
Article number12918
JournalNature communications
Volume7
DOIs
StatePublished - Sep 21 2016

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Cytosine Deaminase
mutagenesis
Mutagenesis
mutations
breast
lungs
Haplotypes
Tumors
Lung Neoplasms
deoxyribonucleic acid
cancer
Breast Neoplasms
Cytosine
DNA
tumors
proteins
Assays
Proteins
Genes
paradoxes

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The DNA cytosine deaminase APOBEC3H haplotype i likely contributes to breast and lung cancer mutagenesis. / 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.

In: Nature communications, Vol. 7, 12918, 21.09.2016.

Research output: Contribution to journalArticle

Starrett, GJ, Luengas, EM, McCann, JL, Ebrahimi, D, Temiz, NA, Love, RP, Feng, Y, Adolph, MB, Chelico, L, Law, EK, Carpenter, MA & Harris, RS 2016, 'The DNA cytosine deaminase APOBEC3H haplotype i likely contributes to breast and lung cancer mutagenesis', Nature communications, vol. 7, 12918. https://doi.org/10.1038/ncomms12918
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. / The DNA cytosine deaminase APOBEC3H haplotype i likely contributes to breast and lung cancer mutagenesis. In: Nature communications. 2016 ; Vol. 7.
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