Abstract
Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression. This occurs through the induction of p21 (CDKN1A) and the recruitment of the repressive DREAM complex to the A3B gene promoter, such that loss of p53 through mutation, or human papilloma virus-mediated inhibition, prevents recruitment of the complex, thereby causing elevated A3B expression and cytosine deaminase activity in cancer cells. As p53 is frequently mutated in cancer, our findings provide a mechanism by which p53 loss can promote cancer mutagenesis.
Highlights
The APOBEC3 family of cytosine deaminases are mediators of intrinsic immunity to retroviruses and endogenous retrotransposons, which act by causing cytosine-touracil (C-to-U) deamination in single-stranded DNA that is generated during reverse transcription [1,2], to promote deleterious mutations
Previous analyses of gene expression datasets have indicated that A3B levels are elevated in breast cancers with somatic mutations in the p53 gene (TP53), compared with tumours with WT TP53 [17,45,46]
To further confirm this relationship by RT-qPCR, we analysed gene expression in RNA prepared from 115 primary breast cancers, collected prior to any therapy
Summary
The APOBEC3 family of cytosine deaminases are mediators of intrinsic immunity to retroviruses and endogenous retrotransposons, which act by causing cytosine-touracil (C-to-U) deamination in single-stranded DNA that is generated during reverse transcription [1,2], to promote deleterious mutations. Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes, in particular AID, have been implicated in the epigenetic regulation of gene expression by directing the deamination of 5-hydroxymethylcytosine generated by TET enzyme conversion of 5-methylcytosine Deamination by AID facilitates base excision repair, resulting in cytosine demethylation. We recently reported a DNA methylation-independent role for A3Bmediated cytidine deamination and repair as a mechanism for chromatin remodelling that facilitates estrogen receptor (ER) target gene expression in breast cancer cells [7]
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