Format

Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):9908-13. doi: 10.1073/pnas.1508040112. Epub 2015 Jul 27.

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

Author information

  • 1Instituto 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;
  • 2Instituto 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.
  • 3Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) - CSIC, 41092 Sevilla, Spain;
  • 4Instituto 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.

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.

KEYWORDS:

ITC; NMR; SET-TAF-Iβ; cytochrome c; histone chaperone

PMID:
26216969
[PubMed - indexed for MEDLINE]
PMCID:
PMC4538685
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk