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

Nucleic Acids Res. 2017 Nov 2;45(19):11056-11069. doi: 10.1093/nar/gkx721.

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.

MeSH terms

  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Humans
  • Immunoblotting
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / metabolism
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Minor Histocompatibility Antigens
  • Tumor Suppressor Protein p53
  • APOBEC3B protein, human
  • Cytidine Deaminase