DNA Deamination Is Required for Human APOBEC3A-Driven Hepatocellular Carcinoma In Vivo

Abstract

Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism.

APOBEC3 mutagenesis drives therapy resistance in breast cancer

“…S3c). Similar negative selection against A3A expression has been reported earlier 32,37 . We performed WGS of parent and daughter clones and analyzed acquired alterations.…”

“…Out of the eleven APOBEC family members, A3A and A3B have emerged as the major drivers of APOBEC3 mutagenesis [32][33][34][35][36] . To assess the expression of these proteins among breast cancers harboring APOBEC3 mutational signatures, we utilized immunohistochemistry (IHC) to stain 130 tissue samples using an A3A-specific antibody 37 or an antibody that detects A3A/B/G 38 (Fig. 2a).…”

Human APOBEC3B promotes tumor development in vivo including signature mutations and metastases

“… 13 Importantly, liver tumor formation in this model system requires A3A catalytic activity. 14 However, expression of human A3A is rapidly selected against and lost early in hepatocellular carcinoma development, which limits the potential for longer-term studies on tumor evolution. Moreover, A3B expression is aphenotypic over the same duration in the Fah system.…”

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

“…More recent research also points at a prominent role of A3A in breast [ 30 ] and other cancers [ 30 – 33 ]. Overexpression of A3A and A3B leads to tumorigenesis in transgenic mouse models [ 24 , 28 , 34 – 35 ]. High levels of A3A and A3B mRNA are also linked to the more aggressive breast cancers, including triple negative cancers [ 36 ].…”