Human APOBEC3B promotes tumor heterogeneityin vivoincluding signature mutations and metastases

Abstract

The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many different cancers. Despite over 10 years of work, a causal relationship has yet to be established between APOBEC3B and any stage of carcinogenesis. Here we report a murine model that expresses tumor-like levels of human APOBEC3B after Cre-mediated recombination. Animals appear to develop normally with full-body expression of APOBEC3B. However, adult males manifest infertility and older animals of both sexes show accelerated rates of tumorigenesis (mostly lymphomas or hepatocellular carcinomas). Interestingly, primary tumors also show overt heterogeneity, and a subset spreads to secondary sites. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Elevated levels of structural variation and insertion-deletion mutations also accumulate in these tumors. Together, these studies provide the first cause-and-effect demonstration that human APOBEC3B is an oncoprotein capable of causing a wide range of genetic changes and driving tumor formation in vivo.

Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A

“…Overexpression of A3A and A3B leads to tumourigenesis in transgenic mouse models. 9,10 Initially, A3B was identified as the primary source of DNA mutations in breast and other cancers, 6,7,11 but more recent research also points to a prominent role of A3A in cancers. [12][13][14] Since A3A and A3B are not essential to primary human metabolism and A3B deletion is prevalent in some populations, 15 their inhibition offers a useful strategy to suppress cancer evolution and thereby make the existing anti-cancer therapies more efficient.…”

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

“…We show that the loss of the central E3 ligases, UBR4, UBR5, and HUWE1 stabilizes A3B and A3H-I proteins, resulting in their accumulation and eventually increased APOBEC-related mutational burden. Our findings reveal a previously unconsidered layer of regulation of cellular A3 protein levels, which may broaden the mutational landscape in late-stage cancer, and affect development of therapy resistance 32,[61][62][63][64] .…”

ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma

“…A separate study, using an independently generated Rosa26-lsl-A3B allele with low expression of A3B similar to ours, also found no evidence of increased mutagenesis in primary tumours but did identify increased mutation burden and evidence of Cytidine mutations in cell lines derived from end-stage KPA tumours (26). A preprint available at the time of writing has now shown that much higher levels of A3B expression, driven from the artificial CAG promoter-enhanced Rosa26 locus, suffice to generate tumours in mice after a protracted latency period of up to 600 days (35). Importantly, this latter study reports successful identification of the canonical C->T APOBEC mutagenesis signature, predominantly in the context of TC dinucleotides conforming to COSMIC base substitution signature SBS02 (36), in tumours from Rosa26.CAG-A3B mice.…”