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

Periyasamy, Manikandan, Singh, Anup K., Gemma, Carolina, Kranjec, Christian, Farzan, Raed, Leach, Damien A., Navaratnam, Naveenan, Pálinkás, Hajnalka L., Vértessy, Beata G., Fenton, TR, and others. (2017) p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells. Nucleic Acids Research, 45 (19). pp. 11056-11069. ISSN 0305-1048. E-ISSN 1362-4962. (doi:10.1093/nar/gkx721) (KAR id:63515)

PDF Publisher pdf Language: English This work is licensed under a Creative Commons Attribution 4.0 International License.
Download this file (PDF/5MB)
Request a format suitable for use with assistive technology e.g. a screenreader
Official URL: http://dx.doi.org/10.1093/nar/gkx721

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.

Item Type:	Article
DOI/Identification number:	10.1093/nar/gkx721
Subjects:	Q Science
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	Tim Fenton
Date Deposited:	21 Sep 2017 13:29 UTC
Last Modified:	05 Nov 2024 10:58 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/63515 (The current URI for this page, for reference purposes)

University of Kent Author Information

Fenton, TR.

Creator's ORCID:	https://orcid.org/0000-0002-4737-8233
CReDIT Contributor Roles:

Depositors only (login required):

Altmetric

Download Statistics

Total unique views for this document in KAR since July 2020. For more details click on the image.