title: CSB protein is (a direct target of HIF-1 and) a critical mediator of the hypoxic response.
abstract: Cockayne syndrome (CS) is a rare genetic disease characterized by neurological problems, growth failure and premature ageing. Many of these features cannot simply be ascribed to the defect that CS cells display during transcription-coupled repair. Here, we show that CSB mutant cells are unable to react to hypoxic stimuli by properly activating the hypoxia-inducible factor-1 (HIF-1) pathway, a defect that is further enhanced in the event of a concomitant genotoxic stress. Furthermore, we show that CSB expression is under the control of HIF-1 and has a critical function during hypoxic response by redistributing p300 between HIF-1 and p53. Altogether, our data demonstrate that CSB is part of a feedback loop mechanism that modulates the biological functions of p53. The outcome of this study provides new insights into the understanding of the molecular basis of the CS phenotype and the involvement of the CSB protein in the hypoxic response pathway.
authors.affiliation: Laboratory of Molecular Cytogenetics and Mutagenesis, Department ABAC, University of Tuscia, Viterbo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Filippi
authors.forename: Paolo
authors.initials: P
authors.lastname: Latini
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Palitti
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Luca
authors.initials: L
authors.lastname: Proietti-De-Santis
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D003057:Cockayne Syndrome / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D000075223:Poly-ADP-Ribose Binding Proteins; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000075223:Poly-ADP-Ribose Binding Proteins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
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