p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells
| Autor: | Periyasamy, Manikandan, Singh, Anup K, Gemma, Carolina, Kranjec, Christian, Farzan, Raed, Leach, Damien A, Navaratnam, Naveenan, Pálinkás, Hajnalka L, Vértessy, Beata G, Fenton, Tim R, Doorbar, John, Fuller-Pace, Frances, Meek, David W, Coombes, R Charles, Buluwela, Laki, Ali, Simak |
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| Přispěvatelé: | Cancer Research UK, Breast Cancer Research Trust, HCA International, Wellcome Trust, Prostate Action, Novartis Pharmaceuticals UK Limited, Imperial College Healthcare NHS Trust- BRC Funding, AstraZeneca UK Limited, Engineering & Physical Science Research Council (E, National Institute for Health Research, Doorbar, John [0000-0002-4027-102X], Apollo - University of Cambridge Repository |
| Rok vydání: | 2017 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Biochemistry & Molecular Biology CYCLE ARREST Immunoblotting 05 Environmental Sciences PROTEIN Cell Line Minor Histocompatibility Antigens Cytidine Deaminase Neoplasms MUTATIONAL PROCESSES Humans INDUCED CYTIDINE DEAMINASE BREAST-CANCER cancer TUMOR-SUPPRESSOR HUMAN EPITHELIAL-CELLS E7 ONCOPROTEIN 08 Information And Computing Sciences Science & Technology Reverse Transcriptase Polymerase Chain Reaction HUMAN-PAPILLOMAVIRUS 06 Biological Sciences HCT116 Cells Gene Expression Regulation Neoplastic Mutation MULTIPLE HUMAN CANCERS RNA Interference Tumor Suppressor Protein p53 Life Sciences & Biomedicine Developmental Biology |
| ISSN: | 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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