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- W2318353059 abstract "Demethylating agents have been reported to be more toxic to p53-deficient cells than wild type (WT) cells in several models. To elucidate the mechanism underlying this phenomenon, we performed microarray-based global gene expression profiling of mouse embryo fibroblasts (MEFs) from p53-WT and p53-null mice with or without 5-aza-2′-deoxycytidine (5-aza-dC) treatment. This analysis revealed two major findings. First, all protein-coding transcripts induced by 5-aza-dC treatment in WT cells were highly expressed and irresponsive to the demethylating agent in untreated p53-deficient cells. This observation defines p53 as a major driver of DNA methylation-dependent gene silencing. Second, death of p53-null cells treated with 5-aza-dC is preceded by strong activation of transcription of interferon (IFN)-responsive genes driven by IFNα induction. Since no obvious candidates for the role of IFN-inducing factors were found among the genes represented on the microarray, we carried out high-throughput sequencing (HTS) of the entire transcriptome of p53-WT and p53-null MEFs, treated or untreated with 5-aza-dC. The HTS results revealed striking transcriptional upregulation of numerous genetic elements belonging to various classes of retrotransposons and non-coding RNAs in p53-null, but not in p53-WT cells, treated with 5-aza-dC. We named this phenomenon of massive induction of transcription of retroelements, which are normally repressed by p53, RETROSIS. Retrosis is likely to be the trigger of the observed IFN response and the mediator of toxicity in p53-null cells treated with 5-aza-dC. These findings define a novel role for p53, acting along with DNA methylation, in regulation of epigenetic silencing of the large proportion of the genome that consists of retroelements and suggest a new evolutionary role for this tumor suppressor. The impact of retrosis in tumor cells deficient in p53 and implications of this phenomenon for the tumor suppressor function of p53 will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2959. doi:1538-7445.AM2012-2959" @default.
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- W2318353059 date "2012-04-15" @default.
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- W2318353059 title "Abstract 2959: p53 as a guardian of genomic junk: A novel role for p53 in epigenetic silencing of retroelements" @default.
- W2318353059 doi "https://doi.org/10.1158/1538-7445.am2012-2959" @default.
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