APOBEC3A drives deaminase mutagenesis in human gastric epithelium

Cancer genomes frequently carry apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-associated DNA mutations, suggesting APOBEC enzymes as innate mutagens during cancer initiation and evolution. However, the pure mutagenic impacts of the specific enzymes among this family remain unclear in human normal cell lineages. Here, we investigate the comparative mutagenic activities of APOBEC3A and APOBEC3B, through whole-genome sequencing of human normal gastric organoid lines carrying doxycycline-inducible APOBEC expression cassettes. Our findings demonstrate that transcriptional upregulation of APOBEC3A leads to the acquisition of a massive number of genomic mutations in just a few cell cycles. In contrast, despite clear deaminase activity and DNA damage, APOBEC3B upregulation does not generate a significant increase in mutations in the gastric epithelium. APOBEC3B-associated mutagenesis remains minimal even in the context of <i>TP53</i> inactivation. Further analysis of the mutational landscape following APOBEC3A upregulation reveals a detailed spectrum of APOBEC3A-associated mutations, including indels, primarily 1 bp deletions, clustered mutations, and evidence of selective pressures acting on cells carrying the mutations. Our observations provide a clear foundation for understanding the mutational impact of APOBEC enzymes in human cells.

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Journal
Genome Research
Published
2025-08-26
DOI
https://doi.org/10.1101/gr.280338.124
Citations
1
Primary Topic
Digestive system and related health
Type
article

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article

APOBEC3A drives deaminase mutagenesis in human gastric epithelium

Bon‐Kyoung Koo, Jie‐Hyun Kim, Yoo Jin Bae, Hyunki Kim et al.
1 citations
Genome Research
Digestive system and related health
article

APOBEC3A drives deaminase mutagenesis in human gastric epithelium

Bon‐Kyoung Koo, Jie‐Hyun Kim, Yoo Jin Bae, Hyunki Kim, Kijong Yi, Joonoh Lim, Jinju Han, Hugo J.G. Snippert, Yohan An, Seongyeol Park, Young Seok Ju, Thomas M. Klompstra, J H Lee, Jeonghwan Youk, Taewoo Kim, Ji‐Hyun Lee, Jung Woo Park, Won Hee Lee, Haeun Lee, Ji‐Hyung Park, Soo A Oh, Chang Hyun Nam
article en
1 citations

Abstract

Cancer genomes frequently carry apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-associated DNA mutations, suggesting APOBEC enzymes as innate mutagens during cancer initiation and evolution. However, the pure mutagenic impacts of the specific enzymes among this family remain unclear in human normal cell lineages. Here, we investigate the comparative mutagenic activities of APOBEC3A and APOBEC3B, through whole-genome sequencing of human normal gastric organoid lines carrying doxycycline-inducible APOBEC expression cassettes. Our findings demonstrate that transcriptional upregulation of APOBEC3A leads to the acquisition of a massive number of genomic mutations in just a few cell cycles. In contrast, despite clear deaminase activity and DNA damage, APOBEC3B upregulation does not generate a significant increase in mutations in the gastric epithelium. APOBEC3B-associated mutagenesis remains minimal even in the context of <i>TP53</i> inactivation. Further analysis of the mutational landscape following APOBEC3A upregulation reveals a detailed spectrum of APOBEC3A-associated mutations, including indels, primarily 1 bp deletions, clustered mutations, and evidence of selective pressures acting on cells carrying the mutations. Our observations provide a clear foundation for understanding the mutational impact of APOBEC enzymes in human cells.

Genome ResearchVol. 35(10)
Pohang University of Science and Technology (KR), Korea Advanced Institute of Science and Technology (KR), University of Patras (GR), Yonsei University (KR), Severance Hospital (KR), Institute for Basic Science (KR), Oncode Institute (NL), NanoCellect Biomedical (United States) (US), Gangnam Severance Hospital (KR), Korea Institute of Science & Technology Information (KR)
Vanderbilt University, Vanderbilt University Medical Center, York University, National Research Foundation, National Research Foundation of Korea, Korea Advanced Institute of Science and Technology, Institute for Basic Science
Digestive system and related health
DOIOpen Access PDFOpenAlex
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