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

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Title: p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells
Authors: Periyasamy, M
Singh, A
Gemma, C
Kranjec, C
Farzan, R
Leach, D
Navaratnam, N
Palinkas, HL
Vertessy, BG
Fenton, TR
Doorbar, J
Fuller-Pace, F
Meek, DW
Coombes, RC
Buluwela, L
Ali, S
Item Type: Journal Article
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.
Issue Date: 16-Aug-2017
Date of Acceptance: 7-Aug-2017
URI: http://hdl.handle.net/10044/1/50376
DOI: https://dx.doi.org/10.1093/nar/gkx721
ISSN: 1362-4962
Publisher: Oxford University Press (OUP)
Start Page: 11056
End Page: 11069
Journal / Book Title: Nucleic Acids Research
Volume: 45
Issue: 19
Copyright Statement: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Cancer Research UK
Breast Cancer Research Trust
HCA International
Breast Cancer Research Trust
Wellcome Trust
Prostate Action
Novartis Pharmaceuticals UK Limited
Cancer Research UK
Cancer Research UK
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
AstraZeneca UK Limited
Cancer Research UK
Engineering & Physical Science Research Council (E
Cancer Research UK
Cancer Research UK
Cancer Research UK
Cancer Research UK
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Cancer Research UK
National Institute for Health Research
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: C1458/A5368
PC2889BCRT
PG0586LH
N/A
081637/Z/06/Z
G2006/13
Neocent Trial
C37/A9356
C37/A11680
13392
RD205
AZ434611
A12992
EP/K503733/1
C42671 / A12991
12993
C42671 / A12990
C37/A18691
18078
RDC02 79560
RDB01 79560
RDB01 79560
RDB01 79560
C24523/A25147
RDB01
RDB01
RDB01
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
INDUCED CYTIDINE DEAMINASE
HUMAN EPITHELIAL-CELLS
MULTIPLE HUMAN CANCERS
HUMAN-PAPILLOMAVIRUS
BREAST-CANCER
MUTATIONAL PROCESSES
TUMOR-SUPPRESSOR
E7 ONCOPROTEIN
CYCLE ARREST
PROTEIN
cancer
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Developmental Biology
Publication Status: Published
Appears in Collections:Division of Surgery
Clinical Sciences
Division of Cancer
Molecular Sciences
Faculty of Medicine



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