title: The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis.
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.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Luengas
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McCann
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Diako
authors.initials: D
authors.lastname: Ebrahimi
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Nuri A
authors.initials: NA
authors.lastname: Temiz
authors.affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Love
authors.affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
authors.forename: Madison B
authors.initials: MB
authors.lastname: Adolph
authors.affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
authors.forename: Linda
authors.initials: L
authors.lastname: Chelico
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Law
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carpenter
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000619:Aminohydrolases / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation
chemical_list: D004247:DNA; C529313:APOBEC3H protein, human; D000619:Aminohydrolases