p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells

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.

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility

“…This patient's genome contains kataegis events (genomic segments containing six or more consecutive mutations with an average inter‐mutation distance of less than or equal to 1,000 bp) and a somatic TP53 mutation (Fig. b ), both of which have been shown to be associated with APOBEC‐related signatures . The germline variant identified in this patient is a variant in RAD50 (double strand break protein (p.D767N, ClinVar RCV000131143.3).…”

“…2b), both of which have been shown to be associated with APOBEC-related signatures. 27,30 The germline variant identified in this patient is a variant in RAD50 (double strand break protein (p.D767N, ClinVar RCV000131143.3). RAD50 protein is critical in the recognition and repair of DNA double-strand breaks.…”

“…Melanoma is one of the most common cancers occurring in adolescent and young adults (AYA, aged 30 years or less) in Western countries. Not only does it account for 11% of all cancers in [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] year olds within the United States, it is also the commonest cause of cancer death in this age group. 1,2 AYA patients diagnosed with localized primary melanoma (AJCC Stage I or II) have higher survival rates compared to older adult patients.…”

Apolipoprotein B mRNA editing enzyme catalytic polypeptide‐like family genes activation and regulation during tumorigenesis

“…50 Mechanism of viral oncoprotein E6/E7-mediated elevated APOBEC3B expression is due to removal of p53-mediated repression of APOBEC3B expression. 51 Interestingly, the promoter regions of APOBEC3 genes contain p53-binding sites; p53 protein is a major transcriptional regulator of APOBEC3 genes in response to chromosomal stress, and p53 activation increases several APOBEC3 mRNAs and protein expression in a cellular context, except for APO-BEC3B expression in a suppressive method. 52 In contrast to wildtype p53 activation, p53 hotspot mutants upregulate APOBEC3B expression in cancer cells.…”

“…In contrast, WT p53 activation suppresses APOBEC3B expression through p21mediated transcriptional suppressive complexes occupancy of promoter region of APOBEC3B. 51,52 AID, activation-induced deaminase; IFN, interferon; TNF, tumor necrosis factor aberrant expression of APOBEC for potential interventions. We are only beginning to appreciate the effects of APOBEC-mediated mutagenesis in cancer; many questions remain to be answered.…”