The study, led by a team at The Institute of Cancer Research, London, in collaboration with scientists at Imperial College London and Cancer Research UK's London Research Institute, used X-ray diffraction and electron microscopy to build up a 3D image of a protein called Arp8. The molecule is a component of the INO80 complex, which regulates how DNA is packaged in cells in a material called chromatin.
Chromatin is assembled from structures called nucleosomes, in which the DNA is wrapped around a histone protein core. Tight packaging of chromatin helps to protect the DNA from damage, but looser packing is required during cellular processes like transcription and DNA repair.
A set of molecular machines called chromatin remodelling complexes, including INO80, control positioning of nucleosomes, and so regulate how tightly the DNA is packaged.
INO80 has previously been implicated in the repair of DNA damage, and cells with faults in the INO80 complex are extra sensitive to chemotherapeutic agents that work by attacking DNA.
The new study sheds light on how INO80 interacts with nucleosomes, revealing a central role that Arp8 plays in the function of the complex by pinpointing the specific interactions between Arp8 and histone proteins within nucleosomes.
Study leader Dale Wigley, professor of structural biology at the ICR, said: "Our study allows us to begin to understand the molecular details of how the INO80 complex interacts with nucleosomes during the DNA damage repair process within cells. Although an important start, this is just one protein in a complex that consists of a dozen proteins so we still have a way to go before we understand fully how INO80 regulates chromatin structure."
- Matheshwaran Saravanan, Jochen Wuerges, Daniel Bose, Elizabeth A. McCormack, Nicola J. Cook, Xiaodong Zhang, and Dale B. Wigley. Interactions between the nucleosome histone core and Arp8 in the INO80 chromatin remodeling complex. PNAS. In production; Early edition, December 3, 2012.
- The research was funded in part by The Wellcome Trust, Cancer Research UK, and the European Molecular Biology Organisation.