Tom Ellenberger, D.V.M., Ph.D.
Raymond H. Wittcoff Professor and Head
Biochemistry and Molecular Biophysics
Biochemistry Program
Molecular Biophysics Program
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Office Phone: 314-747-8893
Lab Phone: 314-362-0722
Other Phone: 314-362-0287
FAX: 314-362-4432
Box: 8231
Lab Address: 2903 South Building
Email: tome@biochem.wustl.edu
Website: http://ellenberger.wustl.edu
Keywords: biochemistry; biophysics; DNA; DNA-protein interactions; structural biology
Short Research Description: Structural biology and biochemistry of DNA repair, replication and recombination; chromosome maintenance. |
Research Abstract:
Our lab studies the "guardians of the genome," enzymes that ensure the faithful transmission of our genetic blueprint to future generations. We are investigating the molecular structures and cellular functions of proteins that participate in multiple aspects of genomic stability, including: (1) DNA replication, (2) DNA repair and recombination, and (3) chromatin maintenance.
The genome is under constant assault from damaging agents. Defects in DNA repair pathways result in higher rates of mutation and chromosomal breakage, and an increased incidence of cancers. Using a structural and biochemical approach, we are investigating how DNA repair enzymes locate sites of damage in a vast excess of normal DNA, the basis for specific removal of damaged DNA, and the mechanisms by which multistep enzymatic repair reactions are coordinated to complete the repair process. We are particularly interested in the enzymes that participate in nucleotide excision repair, DNA crosslink repair and recombination. We are also using high-throughput screening to develop small molecule inhibitors of repair enzymes. Tumor cells that are compromised in one DNA repair pathway may be particularly susceptible to killing by inhibitors of another DNA repair pathway. Reversible, site-specific inhibitors of DNA repair may be useful as therapies that sensitize tumors to DNA damaging drugs.
DNA replication is fundamental for the growth and development of all lifeforms, and requires the complex coordination of multiple enzymes and regulatory proteins. In spite of the cartoons of replication forks that are shown in college textbooks, very little is actually known about the overall organization and molecular architecture of any replication system. Our goal is to characterize the molecular interactions that underlie the coupled synthesis of both DNA strands. To this end, we are working to determine the structure of the entire replication fork using the model system of bacteriophage T7. Unique features of the replication process in prokaryotes are attractive targets for the development of selective antimicrobial agents to treat infectious diseases.
DNA silencing is an important means of controlling gene expression and suppressing aberrant DNA recombination. The mechanisms of silencing and chromatin stability are not well understood in yeast or humans. The SIR proteins of Saccharomyces cerevisiae establish actively transcribed regions and transcriptionally silent regions in chromatin. We are using x-ray crystallography, enzymatic assays, and protein interaction mapping to determine the molecular architecture of these silencing complexes and the role of the SIR2 histone deacetylase during spreading of silent DNA. The human SIR2 homologs, Sirtuins, are critical regulators of lifespan and contribute to the regulation of many essential cell processes including tumor suppression, fat mobilization, insulin regulation, aging, and DNA repair. We are using a multidisciplinary approach to understand how Sirtuins achieve biological specialization. |
Selected Publications:
Aihara H, Huang WM, Ellenberger T. An interlocked dimer of the protelomerase TelK distorts DNA structure for the formation of hairpin telomeres. Mol Cell 2007 27:901-913.
Tsodikov OV, Ivanov D, Orelli B, et al. Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA. EMBO J 2007 26:4768-4776.
Biswas T, Aihara H, Radman-Livaja M, Filman D, Landy A, Ellenberger T. A structural basis for allosteric control of DNA recombination by lambda integrase. Nature 2005 435:1059-1066.
Pascal JM, O'Brien PJ, Tomkinson AE, Ellenberger T. Human DNA ligase I completely encircles and partially unwinds nicked DNA. Nature 2004 432:473-478.
Toth EA, Li Y, Sawaya MR, Cheng Y, Ellenberger T. The crystal structure of the bifunctional primase-helicase of bacteriophage T7. Mol Cell 2003 12:1113-1123. |