DESCRIPTION OF LAB RESEARCH WORK
Our DNA is packaged into chromatin by an approximately equal mass of proteins, which provide a foundation for epigenetic regulation of the genome. The focus of my laboratory is the role of chromatin structure, composition and dynamics in genomic regulation, and our research strategy is to push basic, biomedical and biotechnological fronts in a synergistic fashion. In this regard, we have two main themes that work in unison, both of which rely on exploiting and further developing an in vitro platform for chromatin characterization. We employ X-ray crystallographic, 2D electron microscopy (EM) and cryo-EM (3D) approaches for structural characterization, which is in turn complemented with a variety of methods including cellular imaging and activity experiments. The main objective is to understand how epigenetic factors operate in chromatin regulation, which conversely can be exploited for biotechnological and pharmaceutical applications.
One of our two main research themes is a unique interdisciplinary program for the development of chromatin-targeting anticancer agents and research tools that involves many collaborators around the globe. This entails an atom to cell (and tumor model) approach allowing the directed design of therapeutic candidates and research agents. The second major theme involves materials and methods development and their application for characterizing chromatin dynamics in the context of different transcription and DNA repair factors (especially PARP proteins) and architectural proteins— such as linker histones (compacting agents) and HMGN proteins (unfolding factors).
- Chromatin Higher Order Structure and the Function of Architectural Factors
- Epigenetic Tools and Drugs through Site Selective Targeting of Chromatin
- DNA Repair Factor Activities, Tumor Vulnerabilities & Drug Targeting
- Z. Adhireksan, D. Sharma, P.L. Lee & C.A. Davey. 2020. Near Atomic Resolution Structures of Interdigitated Nucleosome Fibres. Nat. Commun. In press.
- D. Sharma, L. De Falco, S. Padavattan, C. Rao, S. Geifman-Shochat, C.F. Liu & C.A. Davey. 2019. PARP1 Exhibits Enhanced Association and Catalytic Efficiency with gammaH2A.X-Nucleosome. Nat. Commun. 10(1): #5751.
- L. Batchelor, L. DeFalco, T. von Erlach, D. Sharma, Z. Adhireksan, U. Rothlisberger, C.A. Davey & P.J. Dyson. 2019. Cross-Linking Allosteric Sites on the Nucleosome. Angew. Chem. Int. Ed. 58(44): 15660-15664.
- G.E. Davey, Z. Adhireksan, Z. Ma, T. Riedel, D. Sharma, S. Padavattan, D. Rhodes, A. Ludwig, S. Sandin, B.S. Murray, P.J. Dyson & C.A. Davey. 2017. Nucleosome Acidic Patch-Targeting Binuclear Ruthenium Compounds Induce Aberrant Chromatin Condensation. Nat. Commun. 8(1): #1575.
- Z. Adhireksan, G. Palermo, T. Riedel, Z. Ma, R. Muhammad, U. Rothlisberger, P.J. Dyson & C.A. Davey. 2017. Allosteric cross-talk in chromatin can mediate drugdrug synergy. Nat. Commun. 8: #14,860.
- Z. Ma, G. Palermo, Z. Adhireksan, B.S. Murray, T. von Erlach, P.J. Dyson, U. Rothlisberger & C.A. Davey. 2016. An Organometallic Compound Which Exhibits a DNA Topology-Dependent One-Stranded Intercalation Mode. Angew. Chem. Int. Ed. 55(26): 7441-7444.
- E.Y.D. Chua, G.E. Davey, C.F. Chin, P. Dröge, W.H. Ang & C.A. Davey. 2015. Stereochemical Control of Nucleosome Targeting by Platinum-Intercalator Antitumour Agents. Nucleic Acids Res. 43(11): 5284-5296.
- Z. Adhireksan, G.E. Davey, P. Campomanes, M. Groessl, C.M. Clavel, H. Yu, A.A. Nazarov, H.F. Yeo, W.H. Ang, P. Dröge, U. Rothlisberger, P.J. Dyson & C.A. Davey. 2014. Ligand Substitutions between Ruthenium-Cymene Compounds Can Control Protein versus DNA Targeting and Anticancer Activity. Nat. Commun. 5: #3462.
- E.Y.D. Chua, D. Vasudevan, G.E. Davey, B. Wu & C.A. Davey. 2012. The Mechanics Behind DNA SequenceDependent Properties of the Nucleosome. Nucleic Acids Res. 40(13): 6338-6352.
- B. Wu, P. Dröge & C.A. Davey. 2008. Site Selectivity of Platinum Anticancer Therapeutics. Nat. Chem. Biol. 4(2): 110-112.