title: Structural basis for inhibition of the histone chaperone activity of SET/TAF-Iβ by cytochrome c.
abstract: Chromatin is pivotal for regulation of the DNA damage process insofar as it influences access to DNA and serves as a DNA repair docking site. Recent works identify histone chaperones as key regulators of damaged chromatin's transcriptional activity. However, understanding how chaperones are modulated during DNA damage response is still challenging. This study reveals that the histone chaperone SET/TAF-Iβ interacts with cytochrome c following DNA damage. Specifically, cytochrome c is shown to be translocated into cell nuclei upon induction of DNA damage, but not upon stimulation of the death receptor or stress-induced pathways. Cytochrome c was found to competitively hinder binding of SET/TAF-Iβ to core histones, thereby locking its histone-binding domains and inhibiting its nucleosome assembly activity. In addition, we have used NMR spectroscopy, calorimetry, mutagenesis, and molecular docking to provide an insight into the structural features of the formation of the complex between cytochrome c and SET/TAF-Iβ. Overall, these findings establish a framework for understanding the molecular basis of cytochrome c-mediated blocking of SET/TAF-Iβ, which subsequently may facilitate the development of new drugs to silence the oncogenic effect of SET/TAF-Iβ's histone chaperone activity.
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), 41092 Sevilla, Spain;
authors.forename: Katiuska
authors.initials: K
authors.lastname: González-Arzola
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), 41092 Sevilla, Spain; marosa@us.es idiazmoreno@us.es.
authors.forename: Irene
authors.initials: I
authors.lastname: Díaz-Moreno
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) - CSIC, 41092 Sevilla, Spain;
authors.forename: Ana
authors.initials: A
authors.lastname: Cano-González
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), 41092 Sevilla, Spain;
authors.forename: Antonio
authors.initials: A
authors.lastname: Díaz-Quintana
authors.affiliation: Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) - CSIC, 50018 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain; Fundación Agencia Aragonesa para la Investigación y Desarrollo (ARAID), 50018 Zaragoza, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Velázquez-Campoy
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), 41092 Sevilla, Spain;
authors.forename: Blas
authors.initials: B
authors.lastname: Moreno-Beltrán
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) - CSIC, 41092 Sevilla, Spain;
authors.forename: Abelardo
authors.initials: A
authors.lastname: López-Rivas
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), 41092 Sevilla, Spain; marosa@us.es idiazmoreno@us.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: De la Rosa
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D056488:Histone Chaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D014981:Xenopus
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D045304:Cytochromes c; D002166:Camptothecin
keywords: ITC; NMR; SET-TAF-Iβ; cytochrome c; histone chaperone