Structural basis for inhibition of the histone chaperone activity of SET/TAF-Iß by cytochrome c

González-Arzola, K. ; Díaz-Moreno, I. ; Cano-González, A. ; Díaz-Quintana, A. ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Moreno-Beltrán, B. ; López-Rivas, A. ; De la Rosa, Miguel A. ; Fersht, A.R.

Resumen: 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 re- gulators 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 chap- erone SET/TAF-Iß 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-Iß to core histones, thereby locking its histone-binding domains and inhibiting its nucle- osome assembly activity. In addition, we have used NMR spectros- copy, 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-Iß. Overall, these findings estab- lish a framework for understanding the molecular basis of cyto- chrome c-mediated blocking of SET/TAF-Iß, which subsequently may facilitate the development of new drugs to silence the oncogenic effect of SET/TAF-Iß’s histone chaperone activity.

Idioma: Inglés

DOI: 10.1073/pnas.1508040112

Año: 2015

Publicado en: Proceedings of the National Academy of Sciences 112, 32 (2015), 9908-9913
ISSN: 0027-8424

Factor impacto JCR: 9.423 (2015)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 4 / 62 = 0.065 (2015) - Q1 - T1

Factor impacto SCIMAGO: 6.814 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2012-31670
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2012-32824

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)