title: p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs.
abstract: Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine. The abundance of these transcripts exceeded the level of β-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named "TRAIN" (for "transcription of repeats activates interferon"), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Katerina I
authors.initials: KI
authors.lastname: Leonova
authors.forename: Leonid
authors.initials: L
authors.lastname: Brodsky
authors.forename: Brittany
authors.initials: B
authors.lastname: Lipchick
authors.forename: Mahadeb
authors.initials: M
authors.lastname: Pal
authors.forename: Liliya
authors.initials: L
authors.lastname: Novototskaya
authors.forename: Alex A
authors.initials: AA
authors.lastname: Chenchik
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Elena A
authors.initials: EA
authors.lastname: Komarova
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives; D019295:Computational Biology; D019175:DNA Methylation; D000077209:Decitabine; D063185:Epigenetic Repression / Q000235:genetics / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D022661:RNA, Untranslated / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D017423:Sequence Analysis, RNA; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: D000199:Actins; D007370:Interferon Type I; D022661:RNA, Untranslated; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D001374:Azacitidine