RT Journal
A1 An, Yohan
A1 Lee, Ji-Hyun
A1 Lim, Joonoh
A1 Youk, Jeonghwan
A1 Park, Seongyeol
A1 Park, Ji-Hyung
A1 Yi, Kijong
A1 Kim, Taewoo
A1 Nam, Chang Hyun
A1 Lee, Won Hee
A1 Oh, Soo A
A1 Bae, Yoo Jin
A1 Klompstra, Thomas M.
A1 Lee, Haeun
A1 Han, Jinju
A1 Lee, Junehwak
A1 Park, Jung Woo
A1 Kim, Jie-Hyun
A1 Kim, Hyunki
A1 Snippert, Hugo
A1 Koo, Bon-Kyoung
A1 Ju, Young Seok
T1 APOBEC3A drives deaminase mutagenesis in human gastric epithelium
JF Genome Research 
JO Genome Research 
YR 2025 
FD October 01 
VO 35 
IS 10 
SP 2158 
OP 2172 
DO 10.1101/gr.280338.124 
UL http://genome.cshlp.org/content/35/10/2158.abstract 
AB 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 TP53 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.