Dr. Thomas Hollis

Assistant Professor of Biochemistry

B.S., Florida State University, 1992
Ph.D., (Biochemistry) University of Texas at Austin, 1997
American Cancer Society
Postdoctoral Fellow, Harvard Medical School, 1998-2002

Phone: (336) 716-0768
Email: thollis@wfubmc.edu                                                      page updated 01/08

The maintenance of DNA integrity is essential for normal cellular function and for the propagation of the genetic code to successive generations.  A variety of endogenous cellular reagents and exogenous toxins are capable of reacting with and modifying DNA.  These modifications can pose blocks to replicative DNA polymerases and/or interfere with the binding of regulatory proteins to DNA causing wide spread cellular responses.  Repair of lesions in DNA is a critical cellular response mediated by enzymes that can accurately detect, remove and/or correct the damaged bases. 

Research in my laboratory focuses on the structural biology of proteins involved in DNA repair.  We use a combination of X-ray crystallography, biochemistry and molecular biology to address questions of DNA damage recognition and repair by proteins.  

In collaboration with the Perrino Laboratory we are determining the X-ray crystal structures of the 3’-5’ DNA exonucleases TREX1 and TREX2.  Our goal is to understand how the dimeric structure of these proteins contributes to their substrate specificity and catalytic activity.

Additionally, we are working on determining the structures and functions of proteins involved in the cancer susceptibility syndrome, Fanconi anemia.  This rare disease is a result of the cell’s inability to recognize or repair certain types of DNA damage, particularly interstrand crosslinks.

People in the Lab : Biochemistry Dept : Center for Structural Biology 

Publications:

Lee-Kirsch, MA., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y.A., de Silva, U., Bailey, S.L., Witte, T., Vyse, T.J., Kere, J., Pfeiffer, C., Harvey, S., Wong, A., Koskenmies, S., Hummel, O., Rohde, K., Schmidt, R.E., Dominiczak, A.F., Gahr, M., Hollis, T., Perrino, F.W., Lieberman, J., Hubner, N. (2007) Mutations in the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nature Genetics, 39, 1065-7. (PDF)

Lee-Kirsch, MA., Chowdhury, D., Harvey, S., Gong, M., Senenko, L., Engel, K., Pfeiffer, C., Hollis, T., Gahr, M., Perrino, F.W., Lieberman, J., Hubner, N. (2007) A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med., 85, 531-537. (PDF)

Metz, A.H., Hollis, T., & Eichman, B.F. (2007) DNA damage recognition and repair by 3-methyladenine DNA glycosylase I (Tag), EMBO J., 26, 2411-2420. (PDF)

Rice, G., Newman, W.G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A.L., Bowden, A.P., Perrino, F.W., Lindahl, T., Barnes, D.E., Crow, Y.J. (2007) Heterozygous Mutations in TREX1 cause Familial Chilblain Lupus and Dominant Aicardi-Goutieres Syndrome. Am. J. Hum. Genet., 80, 811-815. (PDF)

De Silva, U., Choudhury, S., Bailey, S.L.,Harvey, S., Perrino, F.W., & Hollis, T. (2007) The crystal structure of TREX1 explains the 3’ nucleotide specificity and reveals a polyproline II helix for protein partnering. J.Biol Chem, 282, 10537-10543. (PDF)

Perrino, F.W., Harvey, S., McMillan, S., & Hollis, T. (2005) The human TREX2 3'→5' exonuclease structure suggests a mechanism for efficient non-processive DNA catalysis. J. Biol. Chem. 280, 15212-15218. (PDF)

Perrino, F.W., Krol, A., Harvey, S., Zheng, S.L., Horita, D.A., Hollis, T., Meyers, D.A., Isaacs, W.B., Xu, J. (2004) Sequence variants in the 3'→5' deoxyribonuclease TREX2: identification in a genetic screen and effects on catalysis by the recombinant proteins. Advan. Enzyme Regul. 44, 37-49. (PDF)

Rezende, L.F., Hollis, T., Ellenberger, T., & Richardson, CC. (2002) Essential Amino Acid Residues in the Single-Stranded DNA-binding Protein of Bacteriophage T7. J. Biol. Chem. 277, 50643-50653. (PDF)

Hollis, T., Stattel, J.S., Walther, D.S., Richardson, C.C., & Ellenberger, T. (2001) Structure of the gene 2.5 protein, a Single-Stranded DNA Binding Protein Encoded by Bacteriophage T7. Proc. Natl. Acad. Sci. USA 98, 9557-956. (PDF)

Hollis, T., Ichikawa, Y. & Ellenberger, T. (2000) DNA Bending and a Flip-out Mechanism for Base Excision by the Helix-hairpin-Helix DNA Glycosylase, Escherichia coli AlkA. EMBO J. 19, 758-766. (PDF)

Hollis, T., Lau, A. & Ellenberger, T. (2000) Structural Studies of Human Alkyladenine Glycosylase (AAG) and E. coli 3-methyladenine glycosylase (AlkA). Mutat. Res. 460, 201-210. (PDF)

Hollis, T., Monzingo, A.F., Bortone, K. & Robertus, J.D. (2000) Crystal Structure of a Chitinase from Coccidioides immitis. Protein Science 9, 544-551. (PDF)  

Hollis, T., Monzingo, A.F., Bortone, K., Schelp, E., Cox, R. & Robertus, J.D. (1998) Crystallization and Preliminary X-ray analysis of a Chitinase from the Fungal Pathogen Coccidioides immitis. Acta Cryst D  D54, 1412-1413

Yan, X., Day, P., Hollis, T., Monzingo, A.F., Schelp, E., Robertus, J.D., Wang, S., and Milne, G.W. (1998) Recognition and Interaction of small rings with the ricin A chain binding site. Proteins 31, 33-41

Hollis, T., Honda, Y., Fukamizo, T., Marcotte, E., Day, P.J. & Robertus, J.D. (1997) Kinetic Anaylysis of Barley Chitinase. Arch. Biochem. Biophys. 344, 335-342

Yan, X., Hollis, T., Svinth, M., Day P., Monzingo, A.F., Milne, G.W. & Robertus, J.D.(1997) Structure-Based Identification of a Ricin Inhibitor. J. Mol. Biol. 266, 1043-1049