TY  - JOUR
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
Y1  - 2025/10/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 2158 
EP  - 2172 
DO  - 10.1101/gr.280338.124 
VL  - 35 
IS  - 10 
UR  - http://genome.cshlp.org/content/35/10/2158.abstract 
N2  - 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. 
ER  -