个人简介

2000 Ph.D. University of Minnesota 1994 B.A. Macalester College, St. Paul, Minnesota

研究领域

Chemical Biology and Biotechnology

The interests of Prof. Beuning’s lab are to understand cellular responses to DNA damage. All organisms experience damage to their genetic material from environmental and endogenous sources. Multiple systems exist to identify and remove damaged bases from DNA in organisms from bacteria to humans. For example, the bacterial SOS response, involving the upregulation of at least 50 genes in E. coli, is induced when cells experience damage to their DNA and other stresses. Many of the genes induced as part of the SOS response are responsible for DNA repair and cell cycle regulation. Another group of genes induced as part of the SOS response, encoding Y family DNA polymerases, play a role in tolerance to DNA damaging agents at a potentially mutagenic cost. The Y family DNA polymerases are specialized DNA polymerases that are able to replicate a wide array of damaged DNA substrates, including thymine-thymine dimers, nucleotide base adducts, and abasic sites. The presence of Y family polymerases in cells confers resistance to several classes of DNA damaging agents and environmental toxins. Because they can engage in mutagenic replication of DNA, Y family DNA polymerases are also linked to antibiotic resistance and cancer. A major focus of our research is to understand the specificity of these DNA polymerases for their damaged DNA substrates using protein engineering, molecular modeling and chemical synthesis. A second focus of the lab is on the dynamics of proteins that regulate DNA damage responses. We are probing the activities of the small protein UmuD that undergoes a self-cleavage reaction and regulates mutagenesis in bacteria through its interactions with Y family DNA polymerases. We also study the dynamics and functions of protein clamps that encircle DNA, providing highly processive and efficient DNA replication by tethering DNA polymerases to their DNA substrates. Using biochemical, biophysical, and genetic approaches, we are investigating the molecular mechanisms by which processivity clamp proteins coordinate the cellular responses to DNA damage and mediate interactions between damage response networks and DNA replication.

近期论文

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"Biochemical Functional Predictions for Protein Structures of Unknown or Uncertain Function" Caitlyn L. Mills, Penny J. Beuning, and Mary Jo Ondrechen Computational and Structural Biotechnology Journal accepted, in press (2015) "Prediction of Distal Residue Participation in Enzyme Catalysis" Heather R. Brodkin, Nicholas A. DeLateur, Srinivas Somarowthu, Caitlyn L. Mills, Walter R. Novak, Penny J. Beuning, Dagmar Ringe, and Mary Jo Ondrechen Protein Science accepted, in press (2015) http://dx.doi.org/10.1002/pro.2648 "Steric gate residues of Y-family DNA polymerases DinB and pol kappa are crucial for dNTP-induced conformational change" Philip Nevin, John R. Engen, and Penny J. Beuning DNA Repair accepted, in press (2015) http://dx.doi.org/10.1016/j.dnarep.2015.01.012 "Structure activity relationship study of Mezzettiasides natural products and their four new disaccharide analogues for anticancer/antibacterial activity" Sumit O. Bajaj, Pei Shi, Penny J. Beuning and George A. O’Doherty MedChemComm 5 1138-1142 (2014) http://dx.doi.org/10.1039/C4MD00095A "Cryptocaryol Structure-Activity Relationship Study of Cancer Cell Cytotoxicity and Ability to Stabilize PDCD4" Michael F. Cuccarese, Yanping Wang, Penny J. Beuning and George A. O’Doherty ACS Medicinal Chemistry Letters 5 522-526 (2014) http://dx.doi.org/10.1021/ml4005039 "Conformational analysis of processivity clamps in solution demonstrates that tertiary structure does not correlate with protein dynamics" Jing Fang, Philip Nevin, Visvaldas Kairys, Ceslovas Venclovas, John R. Engen and Penny J. Beuning Structure 22 572-581 (2014) http://dx.doi.org/10.1016/j.str.2014.02.001 http://www.cell.com/structure/abstract/S0969-2126(14)00040-9 Preview: http://dx.doi.org/10.1016/j.str.2014.03.006 "Use of FRET to study dynamics of DNA replication" Philip Nevin and Penny J. Beuning in Chemical Biology of Nucleic Acids: Fundamentals and Clinical Applications V.A. Erdmann, W.T. Markiewicz, and J. Barciszewski, Eds., Springer, New York, NY 95-111 (2014) View book "Polymerase manager protein UmuD directly regulates E. coli DNA polymerase III α binding to ssDNA" Kathy R. Chaurasiya, Clarissa Ruslie, Michelle C. Silva, Lukas Voortman, Philip Nevin, Samer Lone, Penny J. Beuning, and Mark C. Williams Nucleic Acids Research 41 8959-8968 (2013) http://dx.doi.org/10.1093/nar/gkt648 "Discrimination against major groove adducts by Y family polymerases of the DinB subfamily" Jason M. Walsh, Paul J. Ippoliti, Erin A. Ronayne, Eriks Rozners, and Penny J. Beuning DNA Repair 12 713-722 (2013) http://dx.doi.org/10.1016/j.dnarep.2013.05.006 "Chapter 486 UmuC D Lesion Bypass DNA Polymerase V" Lisa A. Hawver and Penny J. Beuning; in Encyclopedia of Biological Chemistry 2nd edition W. J. Lennarz and M. D. Lane, Eds., Elsevier Science, Vol. 4, 477-481 (2013). (encyclopedia chapter) "Dimer exchange and cleavage specificity of the DNA damage response protein UmuD" Jaylene N. Ollivierre, Jacquelyn L. Sikora, and Penny J. Beuning Biochimica et Biophysica Acta-Proteins and Proteomics 1834 611–620 (2013) http://dx.doi.org/10.1016/j.bbapap.2012.11.008 "Structure Activity Relationship Study of the Cleistriosides and Cleistetrosides for Antibacterial/Anticancer Activity" Pei Shi, Michelle C. Silva, Hua-Yu Wang, Bulan Wu, Novruz Akhmedov, Miaosheng Li, Penny J. Beuning, George A. O'Doherty, ACS Medicinal Chemistry Letters 3 1086–1090 (2012) http://dx.doi.org/10.1021/ml300303g "Multiple strategies for translesion synthesis in bacteria" Paul Ippoliti, Nicholas A. DeLateur, Kathryn M. Jones, Penny J. Beuning Cells 1 799-831 (2012) http://dx.doi.org/10.3390/cells1040799 "Effects of non-catalytic, distal amino acid residues on activity of E. coli DinB (DNA Polymerase IV) " Jason M. Walsh, Ramya Parasuram, Pradyumna R. Rajput, Eriks Rozners, Mary Jo Ondrechen and Penny J. Beuning Environmental and Molecular Mutagenesis 53 766-776 (2012) http://dx.doi.org/10.1002/em.21730 "Synthetic nucleotides as probes of DNA polymerase specificity" Jason M. Walsh and Penny J. Beuning, Journal of Nucleic Acids 2012 530963 (2012) http://dx.doi.org/10.1155/2012/530963 "Selective disruption of the DNA polymerase III α-β complex by the umuD gene products" Michelle C. Silva, Philip Nevin, Erin A. Ronayne, and Penny J. Beuning, Nucleic Acids Research 40 5511-5522 (2012) http://dx.doi.org/10.1093/nar/gks229 "De Novo Asymmetric Synthesis of Fridamycin E" Qian Chen, Michael Mulzer, Pei Shi, Penny J. Beuning, Geoffrey W. Coates, and George A. O’Doherty Organic Letters 13 6592-6595 (2011) http://dx.doi.org/10.1021/ol203041b "A Tale of Two Isomerases: Compact versus Extended Active Sites in Ketosteroid Isomerase and Phosphoglucose Isomerase" Srinivas Somarowthu, Heather R. Brodkin, J. Alejandro D'Aquino, Dagmar Ringe, Mary Jo Ondrechen, Penny J. Beuning Biochemistry 50 9283–9295 (2011) http://dx.doi.org/10.1021/bi201089v "Electron spin labeling reveals the highly dynamic N-terminal arms of the SOS mutagenesis protein UmuD" Jaylene N. Ollivierre, David E. Budil, and Penny J. Beuning Molecular BioSystems 7 3183-3186 (2011) dx.doi.org/10.1039/C1MB05334E "Characterization of Escherichia coli UmuC Active Site Loops Identifies Variants that Confer UV Hypersensitivity" Lisa A. Hawver, Caitlin A. Gillooly, and Penny J. Beuning Journal of Bacteriology 193 5400-5411 (2011) dx.doi.org/10.1128/JB.05301-11