Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
MARK D. SUTTON, Ph.D.
Associate Professor
Regulation and coordination of DNA replication, DNA repair and DNA damage tolerance.
Genomic integrity depends upon not only high fidelity DNA replication, but also on a variety of highly accurate DNA repair processes, as well as DNA damage tolerance mechanisms that act to catalyze replication over DNA lesions that cannot be repaired. We are interested in developing an integrated mechanistic view of how organisms coordinate the actions of their replication machinery with those of other cellular factors involved in DNA repair and damage tolerance. My lab utilizes a combination of biochemical and genetic approaches to investigate the molecular mechanisms of DNA replication and DNA repair in Escherichia coli. Current efforts are focused on understanding the mechanisms by which the actions of high fidelity and error-prone lesion bypass DNA polymerases are coordinated with each other, as well as other proteins involved in DNA metabolism. As part of this work, we are determining the mechanisms by which these proteins ‘switch’ places with each other at a replication fork. We are particularly interested in understanding the contribution of these switches to DNA fidelity and DNA damage tolerance.
Mechanisms underlying clonal expansion and pathoadaptation in Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a gram-negative human opportunistic pathogen that chronically infects immunocompromised individuals, and is the leading cause of morbidity and mortality for cystic fibrosis (CF) patients. CF is an inherited, chronic disease affecting primarily the lungs and digestive system. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the lungs, mutations in CFTR lead to the accumulation of thick mucous, which predisposes these individuals to P. aeruginosa infections. One remarkable feature of P. aeruginosa is its ability to undergo clonal expansion during chronic infection. Clonal expansion refers to the process by which a population of P. aeruginosa cells undergoes continual selection for the accumulation of specific genetic changes that collectively promote its long-term survival and enhance pathogenesis. We are interested in understanding the mechanisms that contribute to DNA mutagenesis in P. aeruginosa, and are particularly interested in determining the contribution of these mechanisms to clonal expansion and pathoadaptation. Current efforts are focused on utilizing a combination of genetic and biochemical approaches to determine the roles of mismatch repair, base excision repair, and error-prone DNA polymerases in spontaneous and DNA damage-induced mutagenesis.
Selected Recent PublicationsSutton, M. D. (2009) Coordinating DNA polymerase traffic during high and low fidelity synthesis. BBA – Proteins and Proteomics. In press.
Heltzel, J. M. H., Maul, R. W., Scouten Ponticelli, S. K., and Sutton M. D. (2009) A model for DNA polymerase switching involving a single cleft and the rim of the sliding clamp. Proc. Nat. Acad. Sci. U.S.A. 106:12664-12669.
Sanders, L. H., Sudhakaran, J. and Sutton, M. D. (2009) The GO system prevents ROS-induced mutagenesis and killing in Pseudomonas aeruginosa. FEMS Microbiol Lett. 294:89-96.
Scouten Ponticelli, S. K., Duzen, J. M., and Sutton, M. D. (2009) Contributions of the individual hydrophobic clefts of the Escherichia coli beta sliding clamp to clamp loading, DNA replication and clamp recycling. Nucleic Acids Res. 37:2796-2809.
Heltzel, J. M. H., Scouten Ponticelli, S. K., Sanders, L. H., Duzen, J. M., Cody, V., Pace, J., Snell, E., and Sutton, M. D. (2009) Sliding clamp-DNA interactions are required for viability and contribute to DNA polymerase management in Escherichia coli. J. Mol. Biol. 387:74-91.
Hassett, D. J., Sutton, M. D., Schurr, M. J., Rowe, J. J., Herr, A. B., Caldwell, C. C., and Matu, J. O. (2009) Pseudomonas aeruginosa hypoxic or anaerobic biofilm infections within cystic fibrosis a. Trends in Microbiology. 17:130-138.Sun, J. N., Li, W., Jang, W. S., Nayyar, N., Sutton, M. D., and Edgerton M. (2008) Uptake of the antifungal cationic peptide Histatin 5 by Cadida albicans Ssa2p requires binding to non-conventional sites within the ATPase domain. Mol Microbiol. 70:1246-1260.
Maul, R. W., Scouten Ponticelli, S. K., Duzen, J. M., and Sutton, M. D. (2007) Differential binding of Escherichia coli DNA polymerases to the beta-sliding clamp. Mol Microbiol. 65:811-827.
Maul, R. W., Sanders, L. H., Lim, J. B., Benitez, R., and Sutton, M. D. (2007) Role of Escherichia coli DNA polymerase I in conferring viability upon the dnaN159 mutant strain. J. Bacteriol. 189:4688-4695.
Sanders, L., Rockel, A., Lu, H., Wozniak, D. J., and Sutton, M. D. (2006) Role of the P. aeruginosa dinB-encoded DNA polymerase IV in mutagenesis. J. Bacteriol. 188:8573-8585.
Sutton, M. D. and Duzen, J.M. (2006). Specific amino acid residues in the beta sliding clamp establish a DNA polymerase usage hierarchy in Escherichia coli. DNA Repair. 5:312-323.
Maul, R. W. and Sutton, M. D. (2005). Roles of the Escherichia coli RecA protein and the global SOS response in effecting DNA polymerase selection in vivo. J. Bacteriol. 187:7607-7618.
Sutton, M.D. (2005). Damage signals triggering the E. coli SOS response. In: DNA Damage Recognition, Chapter 35, pages 781-802. Eds. W. Siede, Y. W. Kow, and P. W. Doetsch, Marcel-Decker, Inc., New York, NY.
Yang, F., Jiang, Q., Zhao, J., Ren, Y., Sutton, M. D. and Feng, J. (2005). Parkin stabilizes microtubules through strong binding mediated by three independent domains. J. Biol. Chem. 280:17154-17162.Sutton, M.D., Duzen, J.M. and Maul R.W. (2005). Mutant forms of the Escherichia coli beta sliding clamp that distinguish between its roles in replication and DNA polymerase V-dependent translesion DNA synthesis. Mol. Microbiol. 55:1751-1766.
Sutton, M.D. (2004). The Escherichia coli dnaN159 mutant displays altered DNA polymerase usage and chronic SOS induction. J. Bacteriol. 186:6738-6748.
Duzen, J.M., Walker, G.C. and Sutton, M.D. (2004). Identification of specific amino acid residues in the E. coli beta processivity clamp involved in interactions with DNA polymerase III, UmuD and UmuD’. DNA Repair. 3:301-312.
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