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

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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

Bibliographical note

Funding Information:
The University of Minnesota University Imaging Centers assisted with fluorescent imaging and quantification. Cancer studies in the Harris laboratory have been supported by grants from the Department of Defense Breast Cancer Research Program (BC121347), the Jimmy V Foundation for Cancer Research, and the National Cancer Institute (R21 CA206309). A3H work in the Chelico laboratory is supported by a NSERC Discovery Grant. R.S.H. is an Investigator of the Howard Hughes Medical Institute

Fingerprint Dive into the research topics of 'The DNA cytosine deaminase APOBEC3H haplotype i likely contributes to breast and lung cancer mutagenesis'. Together they form a unique fingerprint.

Cite this