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David Millar, Ph.D.

Professor
Department of Integrative Structural and Computational Biology
California Campus
Laboratory Website
millar@scripps.edu
(858) 784-9870

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Biophysical Chemistry

The focus of our research is on the dynamic structural changes that occur during cellular rearrangements of DNA and during ribozyme catalysis. One project is aimed at understanding the proofreading process that underlies the high DNA replication fidelity of DNA polymerases. Using time-resolved and single molecule fluorescence methods, in conjunction with site-directed mutagenesis procedures, we are elucidating the molecular mechanisms that control the movement of a DNA substrate between the polymerization site of the enzyme and a separate 3’-5’ exonuclease site used in proofreading. We use similar methods to monitor large-scale conformational changes that occur during the catalytic cycle of the hairpin ribozyme, a small endonucleolytic RNA that serves as a model for much larger catalytic RNA molecules. By means of fluorescence resonance energy transfer (FRET) between appropriately placed fluorescent probes, we follow the docking of the substrate-binding and catalytic domains of the ribozyme in real-time and identify nucleotides that stabilize the catalytically active docked conformation. Single-molecule FRET methods are also being applied to Holliday junctions, four-stranded DNA structures that are formed during the course of genetic recombination and related DNA repair events.

Education

Ph.D., California Institute of Technology, 1982

Professional Experience

Editorial Board, Biophysical Journal.
Elected member, Council of the Biophysical Society. 

Member, Macromolecular Structure and Function C study section, NIH.

Selected References

Stengel, G., Gill, J. P., Sandin, P., Wilhelmsson, M., Albinsson, B., Norden, B., Millar, D. P.  Conformational dynamics of DNA polymerase probed with a novel fluorescent DNA base analogue.  Biochemistry 46, 12289-12297 (2007).

Pond, S.J., Ridgeway, W., Robertson, R., Wang, J., Millar, D. P.  HIV-1 Rev protein assembles on viral RNA one molecule at a time. Proc. Natl. Acad. Sci. USA 106, 1404-1408 (2009).

Robertson-Anderson, R.M., Wang, J., Edgcomb, S. P., Carmel, A. B., Williamson, J. R., Millar, D. P.  Single-molecule studies reveal that DEAD box protein DDX1 promotes oligomerization of HIV-1 Rev on the Rev Response Element. Jour. Mol. Biol., in press (2011).

M. F. Bailey, M. F.,  E. J. C. Van der Schans, E. J. C., Millar, D. P.  Dimerization of the Klenow fragment of Escherichia coli DNA polymerase I is linked to its mode of DNA binding. Biochemistry 46, 8085-8099 (2007).