Faculty

DNA in the cell of any living organism constantly undergoes chemical modifications caused by mutagenic agents, sun radiation, active oxygen species etc. If a DNA lesion is not repaired in a proper and timely fashion, mutations leading to developmental disorders, cancers and cell death can arise. On the other hand, repair of DNA lesions caused by cancer chemotherapeutic drugs such as cisplatin results in undesirable resistance of malignant tumors to therapy and therefore DNA repair and replication in these situations needs to be inhibited. Research in our laboratory is focused on function and structure of proteins involved in DNA replication and repair. Specifically, we are interested in two areas:

1. Helicases involved in DNA initial steps of nucleotide excision repair (NER) and transcription in mammals. Our enzymatic and structural (X-ray crystallography) studies of these helicases are aimed at understanding underlying mechanisms of helicase action and ways of inhibiting it in a specific fashion.

2.   A multiprotein machinery that initiates DNA replication in bacteria, which we call a bacterial primosome. Understanding mechanistic and structural details of DNA replication will eventually lead to the discovery of DNA replication inhibitors, which will serve as leads for design of novel antibiotics.

In our research, we use experimental molecular biology (cloning, protein expression and purification), biochemical (enzymatic assays in solution) and biophysical (fluorescence spectroscopy) methods, applied both quantitatively and in a high-throughput fashion, to study helicase action in solution in combination with X-ray crystallography to obtain structural snapshots of multi-step, multi-macromolecular mechanisms involving DNA binding proteins.

Awards

Vahlteich Research Award, College of Pharmacy, University of Michigan, 2007

Representative Publications

1. Biswas, T. and Tsodikov O.V. "Hexameric ring structure of the N-terminal domain of Mycobacterium tuberculosis DnaB helicase", FEBS J, 2008, 275, 3064-3071.

2. Ivanov, D., Tsodikov, O.V., Kasanov, J., Ellenberger, T., Wagner, G. and Collins, T. "Domain-swapped dimerization of the HIV-1 capsid C-terminal domain", Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 4353.

3. Pascal, J. M., Tsodikov, O.V., Hura, G.L., Song, W., Cotner, E.A., Classen, S., Tomkinson, A.E., Tainer, J.A. and Ellenberger, T.  "A Flexible Interface between DNA Ligase and PCNA Supports Conformational Switching and Efficient Ligation of DNA", Mol. Cell, 2006, 24, 279.

4. Tsodikov, O.V., Enzlin, J.H., Scharer, O.D. and Ellenberger, T. "Crystal structure and DNA binding functions of ERCC1, a subunit of the DNA structure-specific endonuclease XPF-ERCC1", Proc. Natl. Acad. Sci. U.S.A., 2005, 102, 11236.

5. Cox, J.M., Tsodikov, O.V. and Cox, M.M. "Organized unidirectional waves of ATP hydrolysis within a RecA filament", PLoS Biol., 2005, Feb3(2): e52.

6. Saecker, R.M., Tsodikov, O.V., Capp, M.W. and Record, M.T., Jr. "Rapid quench mixing to quantify kinetics of steps in association of Escherichia coli RNA polymerase with promoter DNA", Methods Enzymol., 2003, 370, 535.

7. Saecker, R.M., Tsodikov, O.V., McQuade, K.L., Schlax, P.E., Jr., Capp, M.W. and Record, M.T., Jr. "Kinetic and structural models of the association of E. coli σ70 RNA polymerase with the λPR promoter: large scale conformational changes in forming the kinetically-significant intermediates", J. Mol. Biol., 2002, 319, 649.