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PAULL, TANYA T

Tanya T Paull

Professor, Professor of Oncology
Molecular Biosciences, Department of Oncology

Burl G. and Lorene L. Rogers Chair in Human Health

Regulation of DNA double-strand break repair and oxidative stress signaling

tpaull@utexas.edu

Phone: 512-232-7802

Office Location
MBB 2.448

Postal Address
2500 SPEEDWAY
AUSTIN, TX 78712

Dr. Paull received her B.S. and M.S. in Biological Sciences from Stanford Univ. in 1991, and received her Ph.D. from UCLA in 1996. Her post-doctoral research with Dr. Martin Gellert at NIH was supported by a fellowship from the Helen Hay Whitney Foundation. Dr. Paull established an independent laboratory in 2000 in the Dept. of Molecular Genetics and Microbiology at the University of Texas at Austin. Her research is aimed toward understanding the mechanisms of DNA double-strand break repair in eukaryotic cells, as well as the intersection between DNA damage, oxidative stress signaling, and protein homeostasis in human cells. She was an Investigator with the Howard Hughes Medical Institute from 2008 through 2019 and is currently the Burl and Lorene Rogers Chair in Human Health and Professor in the Department of Molecular Biosciences.

Research Summary:

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. Loss of the ATM kinase in humans generates early-onset cerebellum-specific neurodegeneration, an outcome that we have linked to an alternative mode of activation of ATM by reactive oxygen species (ROS). We have characterized mechanisms of ATM activation in vitro with purified proteins and also in human cells, where we have identified ROS-activated ATM signaling as an important regulator of protein homeostasis. In recent years we have pursued this aspect of ATM function and protein homeostasis regulation by developing novel methods to isolate and identify aggregated proteins in human cells and human brain tissues using biochemical fractionation and quantitative label-free mass spectrometry. In addition, we have developed fluorescent, live-cell sensors that report binding of disordered proteins and association with DNA lesions in human cell lines in culture. Lastly, we have developed proximity ligation approaches to quantitatively identify chaperone clients in human cells. We are continuing with these efforts to understand how DNA damage and protein homeostasis intersect in human cells and how these outcomes affect both cancer and neurodegeneration.

Publications:

Ryu, S.W., Stewart, R., Pectol, D.C., Ender, N., Wimalarathne, O., Lee, J-H., Zanini, C.P., Harvey, A., Huibregtse, J.M., Mueller, P., and Paull, T.T. (2020) Proteome-wide identification of HSP70/HSC70 Chaperone Clients in Human Cells, PloS Biology 18(7): e3000606. https://doi.org/10.1371/journal.pbio.3000606.

Paiano, J., Wu, W., Yamada, S., Sciascia, N., Callen, E., Paola, Cotrim A., Deshpande, R.A., Maman, Y., Day, A., Paull, T.T., Nussenzweig, A. ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis. (2020) Nat Commun. 2020 Feb 12;11(1):857.

Kao, C.-H., Ryu, S., Kim, M.J., Wen, X., Wimalarathne, O., and Paull, T.T. (2020). Growth-regulated Hsp70 phosphorylation regulates stress responses and prion maintenance. Mol. Cell. Biol. MCB.00628-19.

Deshpande, R.A., Myler, L.R., Soniat, M.M., Makharashvili, N., Lee, L., Lees-Miller, S.P., Finkelstein, I.J., Paull, T.T. DNA-PKcs promotes DNA end processing by MRN and CtIP. (2020) Science Advances 6(2):eaay0922.

Kim, J.J., Lee S.Y., Gong, F., Battenhouse, A.M., Boutz, D.R., Bashyal, A., Refvik, S.T., Chang, C-M., Xhemalce, B., Paull, T.T., Brodbelt, J.S., Marcotte, E.M., and Miller, K.M. (2019) Systematic Bromodomain Protein Screens Identify Homologous Recombination and R-Loop Suppression Pathways Involved in Genome Integrity. Genes & Development 33(23–24):1751–74. https://doi.org/10.1101/gad.331231.119.

Soniat M.M., Myler L.R., Kuo H-C., Paull T.T., Finkelstein I.J. RPA Phosphorylation Inhibits DNA Resection. (2019) Molecular Cell 75, 145-153.

Myler L.R., Soniat M.M., Zhang X., Deshpande R.A., Paull T.T., Finkelstein IJ. Purification and Biophysical Characterization of the Mre11-Rad50-Nbs1 Complex. (2019) Methods Mol Biol.2004:269–287.

Makharashvili, N., Arora, S., Yin, Y., Fu, Q., Wen, S., Lee, J.-H., Kao, C.-H., Leung, J.W.C., Miller, K.M., Paull, T.T. Sae2/CtIP Prevents R-Loop Accumulation in Eukaryotic Cells. eLife 7 (2018). https://doi.org/10.7554/eLife.42733.

Johnson, T.E., Lee, J.-H., Myler, L.R., Zhou, Y., Mosley, T.J., Yang, S.-H., Uprety, N., Kim, J., and Paull, T.T. (2018). Homeodomain Proteins Directly Regulate ATM Kinase Activity. Cell Reports 24, 1471–1483.

Lee, J.-H., Mand, M.R., Kao, C.-H., Zhou, Y., Ryu, S.W., Richards, A.L., Coon, J.J., and Paull, T.T. (2018). ATM directs DNA damage responses and proteostasis via genetically separable pathways. Science Signaling 11(512). pii: eaan5598. doi: 10.1126/scisignal.aan5598.

Hung, P.J., Johnson, B., Chen, B.-R., Byrum, A.K., Bredemeyer, A.L., Yewdell, W.T., Johnson, T.E., Lee, B.J., Deivasigamani, S., Hindi, I., Amatya, P., Gross, M.L., Paull, T.T., Pisapia, D.J., Chaudhuri, J., Petrini, J.H., Mosammaparast, N., Amarasinghe, G.K., Zha, S., Tyler, J.K., and Sleckman, B.P. (2018). MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining. Molecular Cell 71, 332-342.e8.

Zhang, Y., Lee, J.-H., Paull, T.T., Gehrke, S., D’Alessandro, A., Dou, Q., Gladyshev, V.N., Schroeder, E.A., Steyl, S.K., Christian, B.E., and Shadel, G.S. (2018). Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity. Science Signaling 11(538). pii: eaaq0702. doi: 10.1126/scisignal.aaq0702.

Hewitt, S.L., Wong, J.B., Lee, J.H., Nishana, M., Chen, H., Coussens, M., Arnal, S.M., Blumenberg, L.M., Roth, D.B., Paull, T.T., and Skok, J.A.  (2017). The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect. Cell Reports 21, 979-993.

Arora, S., Deshpande, R.A., Budd, M., Campbell, J., Revere, A., Zhang, X., Schmidt, K.H., and Paull, T.T. (2017) Genetic separation of Sae2 nuclease activity from Mre11 nuclease functions in budding yeast. Molecular and Cellular Biology 37: e00156-17.

Myler, L.R., Gallardo, I.F., Deshpande, R.A., Gonzalez, X.B., Kim, Y., Paull, T.T., and Finkelstein, I.J. (2017). Single-molecule imaging reveals how Mre11-Rad50-Nbs1 initiates DNA break repair. Molecular Cell 67, 891-898.

Deshpande, R., Lee, J.-H., and Paull, T.T. (2017). Rad50 ATPase activity is regulated by DNA ends and requires coordination of both active sites. Nucleic Acids Research 45, 5255-5268.

Zhou, Y., Lee, J.H., Jiang, W., Crowe, J.L., Zha, S., and Paull, T.T. (2017). Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM. Molecular Cell 65, 91-104.

Deshpande, R.A., Lee, J.H., Arora, S., and Paull, T.T. (2016). Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts. Molecular Cell 64, 593-606.

Hoa, N.N., Shimizu, T., Zhou, Z.W., Wang, Z.Q., Deshpande, R.A., Paull, T.T., Akter, S., Tsuda, M., Furuta, R., Tsutsui, K., et al. (2016). Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes. Molecular Cell 64, 580-592.

Myler, L.R., Gallardo, I.F., Zhou, Y., Gong, F., Yang, S.H., Wold, M.S., Miller, K.M., Paull, T.T.*, and Finkelstein, I.J*. (2016). Single-molecule imaging reveals the mechanism of Exo1 regulation by single-stranded DNA binding proteins. Proceedings of the National Academy of Sciences of the United States of America 113, E1170-1179. * co-contributing

Broderick, R., Nieminuszczy, J., Baddock, H.T., Deshpande, R.A., Gileadi, O., Paull, T.T., McHugh, P.J., and Niedzwiedz, W. (2016). EXD2 promotes homologous recombination by facilitating DNA end resection. Nature Cell Biol. 18, 271-280.

Zhang, J., Tripathi, D., Jing, J., Alexander, A., Kim, J., Powell, R., Dere, R., Tait-Mulder, J., Lee, J-H., Paull, T.T., Pandita, R.K., Charaka, V., Pandita, T., Kastan, M., and Walker, C. (2015). ATM Functions at the Peroxisome to Induce Pexophagy in Response to ROS. Nature Cell Biol. 17:1259-1269.

Sarangi, P., Steinacher, R., Altmannova, V., Fu, Q., Paull, T.T., Krejci, L., Whitby, M.C., and Zhao, X. (2015). Sumoylation influences DNA break repair partly by increasing the solubility of a conserved end resection protein. PLoS Genetics 11, e1004899.

Hoa, N.N., Kobayashi, J., Omura, M., Hirakawa, M., Yang, S.H., Komatsu, K., Paull, T.T., Takeda, S., and Sasanuma, H. (2015). BRCA1 and CtIP Are Both Required to Recruit Dna2 at Double-Strand Breaks in Homologous Recombination. PloS One 10, e0124495.

Zhou, Y., and Paull, T.T. (2015). Direct measurement of single-stranded DNA intermediates in mammalian cells by quantitative polymerase chain reaction. Anal Biochem 479, 48-50.

 

Parameswaran, B., Chiang, H.C., Lu, Y., Coates, J., Deng, C.X., Baer, R., Lin, H.K., Li, R., Paull, T.T., and Hu, Y. (2015). Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection. Cell Cycle 14, 437-448.

 

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). Catalytic and noncatalytic roles of the CtIP endonuclease in double-strand break end resection. 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 J.33(5):482-500.

Zhou, Y., and Paull, T.T. (2014). Quantitation of DNA double-strand break resection intermediates in human cells. Nucleic Acids Research 42(3):e19.

Barton, O., Naumann, S.C., Diemer-Biehs, R., Kunzel, J., Steinlage, M., Conrad, S., Makharashvili, N., Wang, J., Feng, L., Lopez, B.S., Paull, T.T., Chen, J., Jeggo, P.A. and Lobrich, M. (2014). Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1. The Journal of Cell Biology 206, 877–894.

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. Mol. Cell. Biol. 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. (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.

Bowen, C., Ju, J.H., Lee, J-H., Paull, T.T., and Gelmann, E.P. (2013). Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1. Cell Reports 4, 516-529.

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. J Biol Chem 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 J 32(1):126-39.

Daniel, J.A., Pellegrini, M., Lee, B.S., Guo, Z., Filsuf, D., Belkina, N.V., You, Z., Paull, T.T., Sleckman, B.P., Feigenbaum, L., Nussenzweig, A. (2012) Loss of ATM kinase activity leads to embryonic lethality in mice. J Cell Biol 198(3): 295-304

Gatei, M., Jakob, B., Chen, P., Kijas, A.W., Becherel, O.J., Gueven, N., Birrell, G., Lee, J.H., Paull, T.T., Lerenthal, Y., Fazry, S. Taucher-Scholz, G., Kalb, R., Schindler, D., Waltes, R., Dork, T., and Lavin, M. F. (2011). ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control. J Biol Chem 286, 31542-31556.

Della-Maria, J., Zhou, Y., Tsai, M.S., Kuhnlein, J., Carney, J., Paull, T.T., Tomkinson A (2011) hMre11/hRad50/Nbs1 and DNA ligase III{alpha}/XRCC1 act together in an alternative non-homologous end joining pathway. J Biol Chem. 286(39): 33845-33853.

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.

Shim, E.Y., Chung, W.H., Nicolette, M.L., Zhang, Y., Davis, M., Zhu, Z., Paull, T.T., Ira, G., and Lee, S.E. (2010). Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J 29, 3370-3380.

Demogines, A., East, A.M., Lee, J.H., Grossman, S.R., Sabeti, P.C., Paull, T.T., and Sawyer, S.S. (2010) Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes. PLOS Genetics 6(10):e1001169.

Lee, J.H., Goodarzi, A.A., Jeggo, P.A., and Paull, T.T. (2010) 53BP1 promotes ATM activity through direct interactions with the MRN complex. EMBO J. 29:574-585.

Hopkins, B.B., and Paull, T.T. (2008) The P. furiosus Mre11/Rad50 complex promotes 5’ strand resection at a DNA double-strand break. Cell 135: 250-260.

 

Daniel, J.A., Pellegrini, M., Lee, J-H., Paull, T.T., Feigenbaum, L., and Nussenzweig, A. (2008) Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo.  J. Cell Biol. 183:777-783.

 

Richard D.J., Bolderson, E., Cubeddu, L., Wadsworth, R.I.M., Savage, K., Sharma,  G.G., Nicolette, M.L., Tsvetanov, S., McIlwraith, M.J., Pandita, R., Takeda,  S., Hay, R.T., Gautier, J., West, S.C., Paull, T.T., Pandita, T.K., , White, M.F., and Khanna, K.K. (2008) Evolutionary conserved single stranded DNA binding protein ‘hSSB1’ is critical for genomic stability. Nature 453: 677-681.

Dupre, A., Boyer-Chatenet, L., Sattler, R.M., Modi, A.P., Lee, J.H., Nicolette, M.L., Kopelovich, L., Jasin, M., Baer, R., Paull, T.T., and Gautier, J. (2008). A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat. Chem. Biol. 4, 119-125.

Lengsfeld, B.M., Rattray, A.J., Bhaskara, V., Ghirlando, R., and Paull, T.T. (2007). Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Molecular Cell 28: 638-651.

 

Bhaskara, V., Dupre, A., Lengsfeld, B., Hopkins, B. B., Chan, A., Lee, J. H., Zhang, X., Gautier, J., Zakian, V. A., and Paull, T. T. (2007). Rad50 Adenylate Kinase Activity Regulates DNA Tethering by Mre11/Rad50 complexes. Mol. Cell 25: 647-661.

Hunt, C.R., Pandita, R.K., Laszlo, A., Higashikubo, R., Agarwal, M., Kitamura, T., Gupta, A., Rief, N., Horikoshi, N., Baskaran, R., Lee, J.H., Lobrich, M., Paull, T.T., Roti Roti, J.L., and Pandita, T.K. (2007). Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status. Cancer Res 67: 3010-3017.

Lou, Z., Minter-Dykhouse, K., Franco, S., Gostissa, M., Rivera, M. A., Celeste, A., Manis, J. P., van Deursen, J., Nussenzweig, A., Paull, T. T., Alt, F. W., and Chen, J. (2006). MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 21: 187-200.

Zhang, X. and Paull, T.T. (2005) The Mre11/Rad50/Xrs2 complex and non-homologous end-joining of incompatible ends in S. cerevisiae. DNA Repair 4: 1281-1294.

Gupta, A., Sharma, G.G., Young, C.S., Agarwal, M., Smith, E.R., Paull, T.T., Lucchesi, J.C., Khanna, K.K., Ludwig, T. and Pandita, T.K. (2005) Involvement of Human MOF in ATM Function. Mol. Cell. Biol. 25: 5292-5305.

Lee, J.H. and Paull, T.T. (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science, 308: 551-554.

Costanzo, V., Paull, T.T., Gottesman, M., and Gautier, J. (2004). Mre11 assembles linear DNA fragments into DNA damage signaling complexes. PLoS Biol 2, E110

Lee, J.-H. and Paull, T.T. (2004). The Mre11/Rad50/Nbs1 complex directly promotes ATM kinase activity. Science 304: 93-96.      

Moncalian, G., Lengsfeld, B., Bhaskara, V., Hopfner, K.P., Karcher, A., Alden, E., Tainer, J.A. and Paull, T.T. (2004) The rad50 signature motif: essential to ATP binding and biological function. J Mol. Biol. 335: 937-951.

Lee, J.-H., Ghirlando, R., Bhaskara, V., Hoffmeyer, M.R., Gu, J. and Paull, T.T. (2003) Regulation of Mre11/Rad50 by Nbs1: effects on nucleotide-dependent DNA binding and association with ATLD mutant complexes. J. Biol. Chem. 278: 45171-45181.

 

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