Faculty Profile:

Alan Tomkinson, Ph.D.
Professor
Associate Director of Basic Research, University of Maryland Greenebaum Cancer Center

Radiation Oncology
School of Medicine

410-706-2795

atomkinson@som.umaryland.edu

Research

My laboratory is interested in the interlinked pathways of DNA replication, DNA repair and genetic recombination, which function together to maintain genomic stability in eukaryotes. Defects in these pathways can lead to a decrease in cell viability, an increase in the frequency of carcinogenesis and an increase in the transmission of altered genetic information to the next generation. We have chosen to focus on eukaryotic DNA joining enzymes, DNA ligases, since mutations in the DNA ligase genes of prokaryotes and lower eukaryotes cause genetic instability. Three DNA ligase genes have been identified in the human genome. Since DNA joining is an essential common step in DNA replication, genetic recombination and most DNA repair pathways, the study of DNA ligases has and will continue to provide insights into the molecular mechanisms of these different DNA transactions. A major goal of these studies is to determine the cellular roles of the different mammalian DNA ligases and to use these enzymes as probes to elucidate the molecular mechanisms of replication, repair and recombination pathways.

Publications

Barnes, D.E., Tomkinson, A.E., Lehmann, A.R., Webster, A.D.B. and Lindahl, T. Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA damaging agents. Cell 69: 495-503, (1992).

Tomkinson, A.E., Bardwell, A.J., Bardwell, L., Tappe, N.J. and Friedberg, E.C. Yeast DNA repair and recombination proteins Rad1 and Rad10 constitute a single-stranded DNA endonuclease activity. Nature 362: 860-862, (1993).

Bardwell, A.J., Bardwell, L., Tomkinson, A.E. and Friedberg, E.C. Specific Cleavage of model Recombination and Repair substrates by the Yeast Rad1/Rad10 endonuclease. Science 265: 2082-2085, (1994).

Mackey, Z.B., Ramos, W., Levin, D.S., Walter, C.A., McCarrey, J.R. and Tomkinson, A.E. An alternative splicing event, which occurs in mouse pachytene spermatocytes, generates a form of DNA ligase III with distinct biochemical properties that may function in meiotic recombination. Molec. Cell. Biol. 17: 989-998, (1997).

Montecucco, A., Rossi, R., Levin, D.S., Gary, R., Park, M.S., Motycka, T., Ciarrocchi, G., Villa, A., Biamonti, G., and Tomkinson, A.E. DNA ligase I is recruited to sites of DNA replication by an interaction with proliferating cell nuclear antigen: Identification of a common targeting mechanism for the assembly of replication factories. EMBO J 17: 3786-3795 (1998).

Levin, D.S., McKenna A.E., Motycka, T.A., Matsumoto, Y., and Tomkinson, A.E. Interaction between PCNA and DNA ligase I is critical for joining of Okazaki fragments and long-patch base-excision repair. Current Biology 10(15):919-922 (2000).

Chen, L., Trujillo, K., Ramos, W., Sung, P., and Tomkinson, A.E. Promotion of Dn14-mediated DNA End Joining by the Rad50/Mre11/Xrs2 Complex. Mol. Cell , Vol. 8:1105-1115 (2001).

Tseng, H.-M. and Tomkinson, A.E., Pol4 interacts with Dnl4/Lif1; a functional link between gap-filling and ligation in non-homologous end joining. J. Biol. Chem. Vol. 277: 4630-45637 (2002).

Leppard, J. Dong, Z., Mackey, Z.B. and Tomkinson, A.E. Physical and Functional interaction between DNA ligase IIIa and poly (ADP-ribose) polymerase in the repair of DNA single-strand breaks. Mol. Cell. Biol. 23: 5919-5127 (2003).

Motycka T.A, Bessho T, Post S.M, Sung P, Tomkinson A.E. Physical and Functional Interaction between the XPF/ERCC1 Endonuclease and hRad52. J. Biol Chem. 279: 13634-13639 (2004).

Della, M., Palmbos, P. L., Tseng, H. M., Tonkin, L. M., Daley, J. M., Topper, L. M., Pitcher, R. S., Tomkinson, A. E., Wilson, T. E., and Doherty, A. J. (2004) Science 306, 683-685

Tseng, H. M., and Tomkinson, A. E. (2004) J Biol Chem 279, 47580-47588

Chen, L., Trujillo, K. M., Van Komen, S., Roh, D. H., Krejci, L., Lewis, L. K., Resnick, M. A., Sung, P., and Tomkinson, A. E. (2005) J Biol Chem 280, 2620-2627

Goetz, J. D., Motycka, T. A., Han, M., Jasin, M., and Tomkinson, A. E. (2005) DNA Repair (Amst) 4, 649-654

Hefferin, M. L., and Tomkinson, A. E. (2005) DNA Repair (Amst) 4, 639-648

Levin, D. S., Vijayakumar, S., Liu, X., Bermudez, V. P., Hurwitz, J., and Tomkinson, A. E. (2004) J Biol Chem 279, 55196-55201

Pascal, J. M., O'Brien, P. J., Tomkinson, A. E., and Ellenberger, T. (2004) Nature 432, 473-478

Subramanian, J., Vijayakumar, S., Tomkinson, A. E., and Arnheim, N. (2005) Genetics 171, 427-441

Personal History

College Degree: B.Sc. University of Newcastle upon Tyne, UK
Post Doctoral Degree: Ph.D. University of Newcastle upon Tyne, UK
Fellowship: University of California at Berkeley
Imperial Cancer Research Fund, UK

Laboratory Personnel

Barbara Dziegielewska (Post-doctoral fellow)
Helen Chen (Post-doctoral fellow)
Jinhu Yin (Post-doctoral fellow)
Julie Della-Maria Goetz (Post-doctoral fellow)
Zhiwan Dong (Post-doctoral fellow)
Melissa Hefferin (Graduate student)
Sangeetha Vijayakumar (Graduate student)
Wei Song(Graduate student)
Carol Blanchard (Program Manager)
John O'Neill (Research Assistant)

http://gpilsinside.umaryland.edu/Web%20files/Molecular%20Medicine/tomkinsonlab.jpg

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