Tanya T PaullProfessor
Burl G. and Lorene L. Rogers Chair in Human Health | Lorene Morrow Kelley Endowed Faculty Fellow FundRegulation of DNA double-strand break repair and oxidative stress email@example.com
The University of Texas at Austin
Molecular Biosciences, College of Natural Sciences
Austin, TX 78712
Research in the lab is focused on the DNA damage response in eukaryotic cells, specifically the checkpoint activation and DNA repair responses that occur immediately after the introduction of chromosomal double-strand breaks. Several components of these DNA damage response systems have been implicated as tumor suppressors in mammalian organisms, thus establishing these factors as major targets in the progression from normal to unregulated cell growth.
Current studies in the lab are primarily focused on the biochemical activities of a complex of proteins, Mrell/Rad50/Nbs1 (M/R/N), which are critical components in the repair of DNA double-strand breaks. We study the activities of recombinant M/R/N complexes in vitro to characterize its functions on different types of DNA substrates and recombination intermediates. In addition, in vivo assays in S. cerevisiae are utilized to identify functions of the complex and the effects of mutant complexes in cells. Our overall goal is to decipher the functions of each of these factors at a molecular level in order to understand how they cooperate to guard cells against genetic rearrangements and transformation.
The M/R/N complex works in concert with the Ataxia-Telangiectasia-Mutated (ATM) protein kinase that phosphorylates many downstream targets responsible for checkpoint activation and DNA damage signaling in eukaryotes. We have previously shown that MRN recruits ATM to broken DNA ends and activates its kinase activity at these sites. We are currently investigating the mechanisms through which ATM is activated, how post-translational modifications affect this process, and how other ATM-interacting factors influence its regulation. We have also recently found that ATM can be activated in an MRN-independent manner through direct oxidation. This pathway is important for cellular control of antioxidant functions and for global responses of human cells to reactive oxygen species. The mechanism and targets of ATM activation through this pathway are currently being investigated.
Makharashvili, N., Tubbs, A.T., Yang, S.H., Wang, H., Barton, O., Zhou, Y., Deshpande, R.A., Lobrich, M., Sleckman, B.P., Wu, X., and Paull, T.T. (2014). CtIP is an endonuclease that processes DNA double-strand breaks for homologous recombination. Molecular Cell 54(6): 1022-1023.
Lee, J.-H., Guo, Z., Myler, L.R., Zheng, S., and Paull, T.T. (2014). Direct activation of ATM by resveratrol under oxidizing conditions. PloS ONE 9(6):e97969.
Deshpande, R., Williams, G.J., Limbo, O., Williams, R.S., Kuhnlein, J., Lee, J.-H., Classen, S., Guenther, G., Russell, P., Tainer, J.A., and Paull, T.T. (2014). ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO Journal 33(5):482-500.
Fu, Q., Chow, J, Bernstein, K.A., Makharashvili, N., Arora, S., Lee, C-F., Person, M., Rothstein, R., and Paull, T.T. (2013) Phosphorylation-regulated transitions in oligomeric state control the activity of the Sae2 DNA repair enzyme. Molecular and Cellular Biology 34(5):778-793.
Cannon, B., Kuhnlein, J., Yang, S.H., Cheng, A., Schindler, D., Stark, J.M., Russell, R., and Paull, T.T. (2013). Visualization of local DNA unwinding by Mre11-Rad50-Nbs1 using single-molecule FRET. Proceedings of the National Academy of Sciences of the United States of America 110(47):18868-73.
Zhou, Y., and Paull, T.T. (2014). Quantitation of DNA double-strand break resection intermediates in human cells. Nucleic Acids Research 42(3):e19.
Zhou, Y., and Paull, T.T. (2013). DNA-dependent Protein Kinase regulates DNA end resection in concert with Mre11-Rad50-Nbs1 (MRN) and Ataxia-Telangiectasia-Mutated (ATM). J. Biol. Chem. 288(52):37112-25.
Lee, J-H., Mand, M.R., Deshpande, R.A., Kinoshita, E., Yang, S-H., Wyman, C., and Paull, T.T. (2013). Ataxia Telangiectasia-Mutated (ATM) Kinase Activity Is Regulated by ATP-driven Conformational Changes in the Mre11/Rad50/Nbs1 (MRN) Complex. Journal of Biological Chemistry 288, 12840-12851.
Yang, S-H., Zhou, R., Campbell, J., Chen, J., Ha, T., and Paull, T.T. (2013) The SOSS1 single-stranded DNA binding complex promotes DNA end resection in concert with Exo1. EMBO Journal 32(1):126-39.
Guo, Z., Deshpande, R., and Paull, T.T. (2010). ATM activation in the presence of oxidative stress. Cell Cycle 9(24):4805-11.
Nicolette, M.L., Lee, K., Guo, Z., Rani, M., Chow, J.M., Lee, S.E. and Paull, T.T. (2010) A direct role for Mre11/Rad50/Xrs2 and Sae2 in 5’ strand resection of DNA double-strand breaks. Nature Structural and Molecular Biology 17(12):1478-85.
Guo, Z., Kozlov, S., Lavin, M.F., Person, M.D., and Paull, T.T. (2010) ATM Activation by Oxidative Stress. Science 330:517-521.