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

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 modulate...

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Detalles Bibliográficos
Autores: González Arzola, Katiuska, Díaz Moreno, Irene, Cano González, Ana María, Díaz Quintana, Antonio Jesús, Velázquez Campoy, Adrián, Moreno Beltrán, José Blas, López Rivas, Abelardo, Rosa Acosta, Miguel Ángel de la
Tipo de recurso: artículo
Estado:Versión enviada para evaluación y publicación
Fecha de publicación:2015
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/68902
Acceso en línea:http://hdl.handle.net/11441/68902
https://doi.org/10.1073/pnas.1508040112
Access Level:acceso abierto
Palabra clave:Cytochrome c
Histone chaperone
ITC
NMR
SET-TAF-Iβ
Descripción
Sumario: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.

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