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

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

Author information

1
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
2
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
3
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
4
Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest 1111, Hungary.
5
Laboratory of Genome Metabolism and Repair, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary.
6
School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
7
Division of Cancer Research, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

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.

PMID:
28977491
PMCID:
PMC5737468
DOI:
10.1093/nar/gkx721
[Indexed for MEDLINE]
Free PMC Article

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