Dr. Daniel Simmons

Professor

Contact

Simmons

Office: 213 McKinly Lab
Lab: 257 McKinly Lab

Mailing address:
Department of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716

Office phone: (302) 831-8547
Lab phone: (302) 831-2245
Fax: (302) 831-2281
E-mail: dsimmons@udel.edu
Web: Dr. Simmons' Homepage

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Education

B.S.: Colorado College
Ph.D.: California Institute of Technology
Postdoctoral: National Institutes of Health

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Research Interests

Our laboratory is interested in the structure and function of the simian virus 40 tumor antigen (T antigen) and of cellular proteins that interact with it in virus infected cells. T antigen is a multifunctional phosphoprotein synthesized early in SV40 infection. It is required for virus DNA replication and for the regulation of viral gene expression in infected cells. Its main functions are to serve.as the origin recognition protein and helicase so that replication can initiate at the origin and proceed bidirectionally along the circular DNA genome.

By using a multifaceted biochemical and genetic approach, we are investigating the fine structure and activity of various functional domains of T antigen and correlating this information to the biology of SV40. Our present efforts are focused on T antigen's ability to bind and unwind the origin of replication and on T antigen's role in the initiation and elongation phases of SV40 DNA replication. This viral protein forms a double hexamer over the origin and this structure serves as the helicase that structurally distorts then melts and unwinds the origin. It also functions to separate the DNA strands at replication forks. We have obtained evidence that cellular proteins topoisomerase I (topo I), DNA polymerase α/primase (pol/prim) and replication protein A (RPA) form a complex with hexamers of T antigen to initiate DNA replication. This complex is stabilized by numerous protein-protein and protein-DNA interactions and we are in the process of mapping and characterizing as many of these as possible. We have recently obtained detailed information about how topoisomerase I interacts with T antigen. By studying the effects of various proteins on the assembly of the complex, we have developed a model that describes the order of events at the origin to initiate DNA replication. We are presently testing various aspects of this model and asking how the complex changes during initiation and elongation of DNA replication.

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Teaching

• BISC 280* - Principles of Biotechnology
• BISC 401* - Molecular Biology of the Cell
• BISC 619* - Informational Macromolecules (Gene Expression Laboratory)
• BISC 679* - Virology

*Access to this site has been restricted by Dr. Simmons.

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Research Group

• Erin Foster, B.A. - Graduate Student (B.A., Hood College). Mechanism of origin unwinding and initiation of DNA replication by SV40 T antigen.
• Rupa Roy, B.S. - Research Associate II. Characterization of the Interactions Between SV40 Large T Antigen and Cellular Replication Factors.
• Weiping Wang, B.S. - Graduate Student (B.S., Zhongshan University, China). Mechanism of helicase action by SV40 T antigen.

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Selected Publications

Khopde, S., Roy, R., and Simmons, D.T. The Binding of Topoisomerase I to T Antigen Enhances the Synthesis of RNA-DNA Primers during Simian Virus 40 DNA Replication. Biochemistry, 47: 9653-9660, 2008.

Khopde, S., and Simmons, D.T. Simian virus 40 DNA Replication is Dependent on an Interaction between Topoisomerase I and the C-terminal End of T Antigen. J. Virol., 82:1136-1145, 2008.

Wang, W., Manna, D., and Simmons, D.T. Role of the Hydrophilic Channels of Simian Virus 40 T Antigen Helicase in DNA Replication. J. Virol., 81:4510-4519, 2007.

Simmons, D.T., Gai, D., Parsons, R., Debes, A., and Roy, R. Assembly of the Replication Initiation Complex on SV40 Origin DNA. Nucleic Acids Res., 32:1103-1112, 2004.

Jiao, J., and Simmons, D.T. Nonspecific DNA Binding Activity of Simian virus 40 large T Antigen is Involved in Melting and Unwinding of the Origin. J. Virol., 77:12720-12728, 2003.

Roy, R., Trowbridge, P., Yang, Z., Champoux, J.J., and Simmons, D.T. The Cap Region of Topoisomerase I Binds to Sites Near Each End of Simian Virus 40 T Antigen. J. Virol., 77:9809-9816, 2003.

Prabhu, V.P., Simons, A.M., Iwasaki, H., Gai, D., Simmons, D.T. and Chen, J. p53 Blocks RuvAB Promoted Branch Migration and Modulates Resolution of Holliday Junctions by RuvC. J. Mol. Biol., 316:1023-1032, 2002.

Wu, C., Roy, R., and Simmons, D.T. Role of Single-Stranded DNA Binding Activity of T Antigen in Simian Virus 40 DNA Replication. J. Virol., 75:2839-2847, 2001.

Simmons, D.T. SV40 Large T antigen- Functions in DNA Replication and Transformation. Adv. Virus Res., 55:75-134, 2000.

Gai, D., Roy, R. Wu, C., and Simmons, D.T. Topoisomerase I Associates Specifically with Simian Virus 40 Large T Antigen Double Hexamer-Origin Complexes. J. Virol., 74:5224-5232, 2000.

Trowbridge, P.W., Roy, R. and Simmons, D.T. Human Topoisomerase I Promotes Initiation of SV40 DNA Replication In Vitro. Mol. Cell. Biol., 19:1686-1694, 1999.

Weisshart, K., Taneja, P., Jenne, A. Herbig, U., Simmons, D.T. and Fanning, E. Two regions of SV40 T antigen determine cooperativity of double hexamer assembly on the viral origin of DNA replication and promote hexamer interactions during bidirectional origin DNA unwinding. J. Virol., 73:2201-2211, 1999.

Wu, C., Edgil, D. and Simmons, D.T. The Origin DNA-Binding and Single-Stranded DNA-Binding Domains of Simian Virus 40 Large T Antigen are Distinct. J. Virol., 72:10256-10259, 1998.

Simmons, D.T., Roy, R., Chen, L., and Trowbridge, P.W. The Activity of Topoisomerase I is Modulated by Large T Antigen During Unwinding of the SV40 Origin. J. Biol.Chem., 273:20390-20396, 1998.

Huang, J., Logsdon, N., Schmieg, F.I. and Simmons, D.T. p53-mediated Transcription Induces Resistance of DNA to UV Inactivation. Oncogene, 17:401-411, 1998.

Pommier, Y., Kohlagen, G. Wu, C. and Simmons, D.T. Mammalian DNA Topoisomerase I Activity and Poisoning by Camptothecin are Inhibited by Simian Virus 40 Large T Antigen. Biochemistry, 37, 3813-3823, 1998.

Simmons, D.T., Trowbridge, P.W., and Roy, R. Topoisomerase I Stimulates SV40 T Antigen-mediated DNA Replication and Inhibits T Antigen's Ability to Unwind DNA at Non-origin Sites. Virology, 242, 435-443, 1998.

Chen, L., Joo, W.S., Bullock, P.A., and Simmons, D.T. The N-terminal Side of the Origin-binding Domain of Simian Virus 40 Large T Antigen is Involved in A/T Untwisting. J. Virol., 71, 8743-8749, 1997.

Simmons, D.T., Melendy, T., Usher, D., and Stillman, B. Simian Virus 40 Large T Antigen Binds to Topoisomerase I. Virology, 222, 365-374, 1996.

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