Journal
NUCLEIC ACIDS RESEARCH
Volume 45, Issue 19, Pages 11056-11069Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx721
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Funding
- Cancer Research UK [C37/A18784]
- NIHR Biomedical Research Centre funding scheme
- Department of Health Imperial College Experimental Cancer Medicine Centre (ECMC)
- Rosetrees Trust [JS16/M229-CD1]
- Breast Cancer Now [2010NovPR16]
- Tayside Tissue Bank
- National Research, Development and Innovation Office [K119493]
- Charity Open Access Fund (COAF) via the Imperial College Open Access Fund
- CRUK
- MRC [MC_PC_13050] Funding Source: UKRI
- Cancer Research UK [18784, 13392] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K503733/1] Funding Source: researchfish
- Medical Research Council [MC_PC_13050] Funding Source: researchfish
- Rosetrees Trust [M229-CD1] Funding Source: researchfish
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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.
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