Professor, Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX
I integrate biophysics and biochemistry to help address challenges relevant to medicine and biotechnology. I strive to characterize macromolecular complexes including their conformations and interactions that control biological outcomes to mechanistically inform on cancer biology and treatment strategies. My group does this by developing and employing multi-disciplinary biophysical methods with biological collaborations to join structures to biology. Importantly, my projects inform and cross-pollinate one another, so we are more able to successfully and efficiently understand how macromolecular complexes and pathway intersections impact outcomes in cells and humans. Besides hypothesis-driven research, my laboratory develops advanced technology to bridge the gaps from molecular structure to quantitative, predictive cell biology: we do this by creating, testing, and providing technology for insights on dynamic macromolecular conformations and interactions that impact biological outcomes including structure-based design and microbially-inspired solutions to challenges in human health.
I develop funded programs that focus structural biology on medical relevant challenges, such as my Structural Biology of DNA Repair (SBDR) NCI program project. My RO1 lab projects center on cellular stress responses (DNA repair impacting genome integrity and tumorigenesis, reactive oxygen regulators, pathogenesis factors, metalloenzymes, RNA, plus enzyme and inhibitor design). My research and training includes advanced methods development for technologies defining complexes and conformations in solution and at high resolution. I designed, built, and run the synchrotron beamline SIBYLS at the Advanced Light Source (ALS) to integrate small angle x-ray scattering (SAXS) with high-resolution crystal structures for predictive biology - see www.bl1231.als.lbl.gov/. SIBYLS had ~1200 users in the last 5 years and >15 HHMI groups.
Our work on structural biology and SAXS includes introducing new equations for analyzing X-ray scattering data for flexible macromolecules and complexes. We introduced a novel SAXS invariant, the first discovered since the Porod invariant 60 years ago. Furthermore, we develop new metrics for accurate structures, conformations, and assemblies in solution. Our analyses are providing parameters to better assess flexibility, measure intermolecular distances and data to model agreement, reduce false positives, and define resolution.
The SIBYLS facility I built and run (funded by my IDAT and MINOS programs) supports efficient progress in developing and testing the technologies and in characterizing protein interactions, complexes, and conformations in solution and at high resolution. These resources support our growing interests in applying both solution and single crystal methods to structure-based inhibitor design relevant to developing chemical knockouts to complement genetic knockouts, and as eventual therapeutics. The synergy between basic research and technique advancement is allowing us to contribute to basic knowledge and advances relevant to human diseases.
Overall, my group’s research and technology development aims to bridge the gaps from molecular structure to quantitative, mechanistic, and predictive cell biology for organisms. I view this as the age of cell biology with sequencing advances and systems biology opening doors to game changing contributions to fighting human diseases and applying biotechnology. A missing element needed to make current scientific contributions more powerful is a mechanistic understanding at the molecular level that leverages the sequence information and provides a bottom up quantitative and predictive knowledge to objectively link with top down systems biology. I therefore aim to develop tools and technologies to address biology grand challenges, and to connect dynamic structures to biological outcomes. I apply synthetic biology and inhibitor design to learn more about how biological systems work, and to develop useful agents for medicine and nanotechnology. By leveraging my project efforts by strategic collaborations, my goal is to help apply these advances to therapeutics for pathogenesis, degenerative diseases and cancer, and for biotechnology useful for sustainable health in humans.
|1982||Duke University, Durham, NC, USA, PHD, Biochemistry and Structural Biology|
|1974||Trinity College of Arts and Sciences, Duke University, Durham, NC, USA, BA, Zoology and Anthropology|
|1982-1984||Postdoctoral, Structural Biology, The Scripps Research Institute, La Jolla, CA|
Visiting Professor, Division of Life Sciences, The University of California Lawrence Berkeley National Laboratory, Berkeley, CA, 2000 - 2009
Professor, The Scripps Research Institute, La Jolla, CA, 1994 - 2015
Director, Department of Integrated Diffraction Analysis Technologies Program, The University of California Lawrence Berkeley National Laboratory, Berkeley, CA, 2004 - Present
Director, The University of California Lawrence Berkeley National Laboratory, Berkeley, CA, 2001 - Present
Director, The University of California Lawrence Berkeley National Laboratory, Berkeley, CA, 2000 - Present
Director, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA, 1996 - Present
Robert A. Welch, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 2015 - Present
- Berroyer A, Bacolla A, Tainer JA, Kim N. Cleavage-defective Topoisomerase I mutants sharply increase G-quadruplex-associated genomic instability. Microb Cell 9(3):52-68, 2022. e-Pub 2022. PMID: 35291312.
- Hammel M, Tainer JA. X-ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double-strand break repair impacting cell and cancer biology. Protein Sci 30(9):1735-1756, 2021. e-Pub 2021. PMID: 34056803.
- Hammel M, Rosenberg DJ, Bierma J, Hura GL, Thapar R, Lees-Miller SP, Tainer JA. Visualizing functional dynamicity in the DNA-dependent protein kinase holoenzyme DNA-PK complex by integrating SAXS with cryo-EM. Prog Biophys Mol Biol S0079-6107(20):30091-2, 2021. e-Pub 2020. PMID: 32966823.
- Brosey CA, Houl JH, Katsonis P, Balapiti-Modarage LPF, Bommagani S, Arvai A, Moiani D, Bacolla A, Link T, Warden LS, Lichtarge O, Jones DE, Ahmed Z, Tainer JA. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. Prog Biophys Mol Biol 163:171-186, 2021. e-Pub 2021. PMID: 33636189.
- Ye Z, Xu S, Shi Y, Bacolla A, Syed A, Moiani D, Tsai CL, Shen Q, Peng G, Leonard PG, Jones DE, Wang B, Tainer JA, Ahmed Z. GRB2 enforces homology-directed repair initiation by MRE11. Sci Adv 7(32), 2021. e-Pub 2021. PMID: 34348893.
- Hambarde S, Tsai CL, Pandita RK, Bacolla A, Maitra A, Charaka V, Hunt CR, Kumar R, Limbo O, Le Meur R, Chazin WJ, Tsutakawa SE, Russell P, Schlacher K, Pandita TK, Tainer JA. EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart. Mol Cell 81(14):2989-3006.e9, 2021. e-Pub 2021. PMID: 34197737.
- Zhou J, Gelot C, Pantelidou C, Li A, Yücel H, Davis RE, Farkkila A, Kochupurakkal B, Syed A, Shapiro GI, Tainer JA, Blagg BSJ, Ceccaldi R, D'Andrea AD. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nat Cancer 2(6):598-610, 2021. e-Pub 2021. PMID: 34179826.
- Bacolla A, Sengupta S, Ye Z, Yang C, Mitra J, De-Paula RB, Hegde ML, Ahmed Z, Mort M, Cooper DN, Mitra S, Tainer JA. Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin. Nucleic Acids Res 49(1):221-243, 2021. PMID: 33300026.
- Ye Z, Shi Y, Lees-Miller SP, Tainer JA. Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy. Front Immunol 12:797880, 2021. e-Pub 2021. PMID: 34970273.
- Tsutakawa SE, Bacolla A, Katsonis P, Bralic A, Hamdan SM, Lichtarge O, Tainer JA, Tsai CL. Decoding Cancer Variants of Unknown Significance for Helicase-Nuclease-RPA Complexes Orchestrating DNA Repair During Transcription and Replication. Front Mol Biosci 8:791792, 2021. e-Pub 2021. PMID: 34966786.
- Moiani D, Link TM, Brosey CA, Katsonis P, Lichtarge O, Kim Y, Joachimiak A, Ma Z, Kim IK, Ahmed Z, Jones DE, Tsutakawa SE, Tainer JA. An efficient chemical screening method for structure-based inhibitors to nucleic acid enzymes targeting the DNA repair-replication interface and SARS CoV-2. Methods Enzymol 661:407-431, 2021. e-Pub 2021. PMID: 34776222.
- Thapar R, Wang JL, Hammel M, Ye R, Liang K, Sun C, Hnizda A, Liang S, Maw SS, Lee L, Villarreal H, Forrester I, Fang S, Tsai MS, Blundell TL, Davis AJ, Lin C, Lees-Miller SP, Strick TR, Tainer JA. Mechanism Of Efficient Double-Strand Break Repair By a Long Non-Coding RNA. Nucleic Acids Res 48(19):10953-10972, 2020. PMID: 33045735.
- Hou J, Zhao R, Xia W, Chang CW, You Y, Hsu JM, Nie L, Chen Y, Wang YC, Liu C, Wang WJ, Wu Y, Ke B, Hsu JL, Huang K, Ye Z, Yang Y, Xia X, Li Y, Li CW, Shao B, Tainer JA, Hung MC. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol 22(10):1264-1275, 2020. e-Pub 2020. PMID: 32929201.
- Eckelmann BJ, Bacolla A, Wang H, Ye Z, Guerrero EN, Jiang W, El-Zein R, Hegde ML, Tomkinson AE, Tainer JA, Mitra S. XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells. NAR Cancer 2(3):zcaa013, 2020. e-Pub 2020. PMID: 32776008.
- Tsutakawa SE, Sarker AH, Ng C, Arvai AS, Shin DS, Shih B, Jiang S, Thwin AC, Tsai MS, Willcox A, Her MZ, Trego KS, Raetz AG, Rosenberg D, Bacolla A, Hammel M, Griffith JD, Cooper PK, Tainer JA. Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations. Proc Natl Acad Sci U S A 117(25):14127-14138, 2020. e-Pub 2020. PMID: 32522879.
- Houl JH, Ye Z, Brosey CA, Balapiti-Modarage LPF, Namjoshi S, Bacolla A, Laverty D, Walker BL, Pourfarjam Y, Warden LS, Babu Chinnam N, Moiani D, Stegeman RA, Chen MK, Hung MC, Nagel ZD, Ellenberger T, Kim IK, Jones DE, Ahmed Z, Tainer JA. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. Nat Commun 10(1):5654, 2019. e-Pub 2019. PMID: 31827085.
- Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, Genois MM, Maity R, van Rossum-Fikkert S, Kertokalio A, Romoli F, Ismail A, Ismalaj E, Petricci E, Neale MJ, Bristow RG, Masson JY, Wyman C, Jeggo PA, Tainer JA. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell 53(1):7-18, 2014. e-Pub 2013. PMID: 24316220.
- Rambo RP, Tainer JA. Accurate assessment of mass, models and resolution by small-angle scattering. Nature 496(7446):477-81, 2013. PMID: 23619693.
- Yuan X, Duan Y, Xiao Y, Sun K, Qi Y, Zhang Y, Ahmed Z, Moiani D, Yao J, Li H, Zhang L, Yuzhalin AE, Li P, Zhang C, Badu-Nkansah A, Saito Y, Liu X, Kuo WL, Ying H, Sun SC, Chang JC, Tainer JA, Yu D. Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1. Cancer Discov. e-Pub 2022. PMID: 35420681.
|Title:||Structural Cell Biology of DNA Repair Machines (SBDR)|
|Title:||MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)|
|Title:||Mre11/Rad50/Nbs1 Structural Biology for DNA Damage Responses|
|Title:||Structural Biology of XPB and XPD Helicases|
|Title:||Structural Biochemistry of DNA Dealkylation|
|Title:||IDAT - Integrated diffraction analysis technologies|
|Funding Source:||Dept of Energy|
|Title:||Structural Biochemistry of DNA Base Excision Repair|
|Title:||Fen-1 Complexes and Human Genome Stability|
|Title:||Superoxide Dismutase Structures and Lou Gehrig’s Disease|
|Title:||Type IV Pili & Related Systems|
|Title:||DNA Repair Inhibitors for Cancer Research and Translation|
|Funding Source:||Cancer Prevention & Research Institute of Texas (CPRIT)|
|Title:||Pharmacological Modulation of Poly(ADP-RIBOSE) Metabolism|