An extended APOBEC3A mutation signature in cancer

Adam Langenbucher; Danae Bowen; Ramin Sakhtemani; Elodie Bournique; Jillian F Wise; Lee Zou; Ashok S Bhagwat; Rémi Buisson; Michael S Lawrence

doi:10.1038/s41467-021-21891-0

An extended APOBEC3A mutation signature in cancer

Nat Commun. 2021 Mar 11;12(1):1602. doi: 10.1038/s41467-021-21891-0.

Authors

Adam Langenbucher^#¹, Danae Bowen^#², Ramin Sakhtemani^#^{1

3

4}, Elodie Bournique², Jillian F Wise^{1

3

5

6}, Lee Zou^{7

8}, Ashok S Bhagwat^{9

10}, Rémi Buisson^{11

12}, Michael S Lawrence^{13

14

15}

Affiliations

¹ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
² Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA.
³ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Chemistry, Wayne State University, Detroit, MI, USA.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Department of Cancer Immunology, Institute for Cancer Research, University of Oslo, Oslo, Norway.
⁷ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. lzou1@mgh.harvard.edu.
⁸ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. lzou1@mgh.harvard.edu.
⁹ Department of Chemistry, Wayne State University, Detroit, MI, USA. axb@chem.wayne.edu.
¹⁰ Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA. axb@chem.wayne.edu.
¹¹ Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA, USA. rbuisson@uci.edu.
¹² Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA. rbuisson@uci.edu.
¹³ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. mslawrence@mgh.harvard.edu.
¹⁴ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. mslawrence@mgh.harvard.edu.
¹⁵ Broad Institute of Harvard and MIT, Cambridge, MA, USA. mslawrence@mgh.harvard.edu.

^# Contributed equally.

Abstract

APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, we show that DNA secondary structure is in fact an orthogonal influence on A3A substrate optimality and, surprisingly, can override the TpC sequence preference. VpC (non-TpC) sites in optimal hairpins can outperform TpC sites as mutational hotspots. This expanded understanding of APOBEC mutagenesis illuminates the genomic Twin Paradox, a puzzling pattern of closely spaced mutation hotspots in cancer genomes, in which one is a canonical TpC site but the other is a VpC site, and double mutants are seen only in trans, suggesting a two-hit driver event. Our results clarify this paradox, revealing that both hotspots in these twins are optimal A3A substrates. Our findings reshape the notion of a mutation signature, highlighting the additive roles played by DNA sequence and DNA structure.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence / genetics
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*
Cytidine Deaminase / genetics*
DNA / genetics*
Escherichia coli / genetics
HEK293 Cells
Humans
Minor Histocompatibility Antigens / genetics*
Mutagenesis
Mutation
Neoplasms / genetics
Nucleic Acid Conformation*
Proteins / genetics*

Substances

Minor Histocompatibility Antigens
Proteins
DNA
APOBEC3A protein, human
APOBEC3B protein, human
Cytidine Deaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding