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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. © 2015 The Authors.  Molecular Carcinogenesis  Published by Wiley Periodicals, Inc.

molecular carcinogenesis

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