title: SIRT1 gene expression upon genotoxic damage is regulated by APE1 through nCaRE-promoter elements.
abstract: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein contributing to genome stability via repair of DNA lesions via the base excision repair pathway. It also plays a role in gene expression regulation and RNA metabolism. Another, poorly characterized function is its ability to bind to negative calcium responsive elements (nCaRE) of some gene promoters. The presence of many functional nCaRE sequences regulating gene transcription can be envisioned, given their conservation within ALU repeats. To look for functional nCaRE sequences within the human genome, we performed bioinformatic analyses and identified 57 genes potentially regulated by APE1. We focused on sirtuin-1 (SIRT1) deacetylase due to its involvement in cell stress, including senescence, apoptosis, and tumorigenesis, and its role in the deacetylation of APE1 after genotoxic stress. The human SIRT1 promoter presents two nCaRE elements stably bound by APE1 through its N-terminus. We demonstrate that APE1 is part of a multiprotein complex including hOGG1, Ku70, and RNA Pol II, which is recruited on SIRT1 promoter to regulate SIRT1 gene functions during early response to oxidative stress. These findings provide new insights into the role of nCaRE sequences in the transcriptional regulation of mammalian genes.
authors.affiliation: Department of Biomedical Sciences and Technologies, University of Udine, 33100 Udine, Italy Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Naples, Italy Department of Biomedical and Pharmaceutical Sciences, University of Salerno, 84084 Fisciano (Salerno), Italy Department of Pharmacy, University of Naples "Federico II," 80134 Naples, Italy Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Antoniali
authors.forename: Lisa
authors.initials: L
authors.lastname: Lirussi
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Ambrosio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Carlo
authors.initials: C
authors.lastname: Vascotto
authors.forename: Elena
authors.initials: E
authors.lastname: Casarano
authors.forename: Daniela
authors.initials: D
authors.lastname: Marasco
authors.forename: Andrea
authors.initials: A
authors.lastname: Scaloni
authors.forename: Federico
authors.initials: F
authors.lastname: Fogolari
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000072200:Ku Autoantigen; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; D012319:RNA Polymerase II; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase