APOBEC3G protects the genome of human cultured cells and mice from radiation‐induced damage

Abstract

Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double‐strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild‐type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G‐expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination‐dependent error‐free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

Similar deamination activities but different phenotypic outcomes induced by APOBEC3 enzymes in breast epithelial cells

“…Only A3A, A3B, A3C, and A3H can enter the nucleus ( Vieira and Soares, 2013 ). A3G can enter the nucleus in certain cancer cells after ionizing radiation treatment ( Nowarski et al, 2012 ; Talluri et al, 2021 ; Britan-Rosich et al, 2022 ; Liu et al, 2023 ). A3H has seven major haplotypes, and although all can enter the nucleus to varying degrees, A3H haplotype I (Hap I) is the only one that is predominantly nuclear ( Li and Emerman, 2011 ; Wang et al, 2011 ).…”

Similar deamination activity but different phenotypic outcomes induced by APOBEC3 enzymes in breast epithelial cells

“…Only A3A, A3B, A3C, and A3H can enter the nucleus (Vieira and Soares, 2013). A3G can enter the nucleus in certain cancer cells and after ionizing radiation treatment (Talluri et al, 2021;Britan-Rosich et al, 2022;Liu et al, 2023). A3H has seven major haplotypes and although all can enter the nucleus to varying degrees, A3H Haplotype I (Hap I) is the only one that is predominantly nuclear (Li and Emerman, 2011;Wang et al, 2011).…”