P53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells

Manikandan Periyasamy, Anup K. Singh, Carolina Gemma, Christian Kranjec, Raed Farzan, Damien A. Leach, Naveenan Navaratnam, Hajnalka L. Pálinkás, Beata G. Vertessy, Tim R. Fenton, John Doorbar, Frances Fuller-Pace, David W. Meek, R. Charles Coombes, Laki Buluwela, Simak Ali

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20 Citations (Scopus)

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 overexpression 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.

Original languageEnglish
Pages (from-to)11056-11069
Number of pages14
JournalNucleic acids research
Volume45
Issue number19
DOIs
Publication statusPublished - 2017

ASJC Scopus subject areas

  • Genetics

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    Periyasamy, M., Singh, A. K., Gemma, C., Kranjec, C., Farzan, R., Leach, D. A., Navaratnam, N., Pálinkás, H. L., Vertessy, B. G., Fenton, T. R., Doorbar, J., Fuller-Pace, F., Meek, D. W., Coombes, R. C., Buluwela, L., & Ali, S. (2017). P53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells. Nucleic acids research, 45(19), 11056-11069. https://doi.org/10.1093/nar/gkx721