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Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter

Abstract

Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide. Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53-wildtype) and cancerous (TP53-mutant) human cells and tissues revealed focal cancer-associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. (c) 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

Type Journal
ISBN 1098-2744 (Electronic) 0899-1987 (Linking)
Authors Blackburn, J.?; Roden, D. L.?; Ng, R.?; Wu, J.?; Bosman, A.?; Epstein, R. J.;
Publisher Name MOL CARCINOGEN
Published Date 2016-12-01 00:00:00
Published Volume 55
Published Issue 12
Published Pages 1940-1951
URL http://www.ncbi.nlm.nih.gov/pubmed/26676339
Status Published in-print