Our studies seek to provide a complete and coherent picture of an emerging area of RNA epigenetics at molecular and atomic level with a final goal to develop novel anticancer therapeutics targeting the human RNA methylome and other nucleoprotein assemblies. We employ leading-edge structural biology methods such as X-ray crystallography, NMR, cryo-EM in combination with an array of other biophysical and chemical biology tools to elucidate structures and mechanisms of large nucleoprotein complexes central to normal homeostasis and childhood cancers.
We are particularly interested in understanding the exact mechanisms by which different enzymes and accessory factors cross talk, assemble, and install various covalent chemical modifications on both coding and noncoding RNAs. N6-methyladenosine (m6A) is the most prevalent form of internal post-transcriptional modifications in human mRNAs. The m6A associated complexes drive cellular transformation and sustained oncogenic translation in cancer. A complete structural elucidation of m6A sub-complexes would facilitate designing of therapeutic strategies to selectively target the dysregulated human RNA methylome in cancer. We are also pursuing structural studies on selective RNA binding proteins that promote tumorigenesis in glioblastoma with a final goal to understand their basic mechanisms of action and structure-guided development of new therapies.
Childhood malignancies often display dysregulated transcription, defective DNA repair, elevated chromosomal instability and aberrant RNA splicing programs, which are thought to be driven by chromosomal gene fusions that encode chimeric transcription factors. These fusion oncogenes act as network hubs to regulate a diverse set of biological events in sarcoma cells. Thus, another area of interest in my laboratory is in understanding the structural and mechanistic basis for the synergistic action of chimeric transcription factors and DNA repair enzymes that appear to cause disruptive cellular homeostasis in pediatric sarcomas. An atomic level understanding of the mode of key molecular assemblies and their interplay will reveal yet unknown aspects of disease progression and greatly enhance our understanding of essential molecular partnerships in sarcoma pathogenesis and reveal new therapeutically exploitable vulnerabilities that can be targeted by novel small molecules.
Dr. Yogesh K. Gupta received his Ph.D. under the supervision of Professors Claudio Luchinat and Ivano Bertini at Magnetic Resonance Center (CERM) of the University of Florence, Italy. Building on to his training in structural biology and his interest in tackling large macromolecular protein-nucleic acid complexes, Dr. Gupta joined Professor Aneel Aggarwal’s group at Mount Sinai School of Medicine, New York, NY as a postdoctoral fellow and was later promoted to Instructor, and Research Assistant Professor. He joined the Greehey Children’s Cancer Research Institute in the spring of 2017 as a Principal Investigator in RNA metabolism and pediatric drug discovery program. He is also an Assistant Professor in the Department of Biochemistry and Structural Biology, and an Associate Member of the Cancer Therapy and Research Center (CTRC), a NCI designated cancer center of the UT Health San Antonio MD Anderson Cancer Center.
Dr. Gupta is a structural biologist with expertise in structure determination of large macromolecular complexes. In the past, he has provided important insights into the mechanisms by which large ATP motors (Type III R-M enzyme EcoP15I) assemble and translocate on DNA to help bacteria evade viral infections. Recently, his work has shed new mechanistic insights into human PrimPol, a novel bifunctional enzyme that couples its DNA primase and DNA polymerase activities to maintain genome integrity. PrimPol can bypass ultraviolet light-induced DNA lesions and/or skip them altogether to initiate de novo DNA synthesis downstream to damage. His work on sequence specific RNA and DNA binding proteins has provided the molecular basis to engineer specificities for the development of novel molecular scissors and designer RNA binding scaffolds. In a collaborative effort, he has also helped develop mimetics that block important pathways in cancer, such as a Ras inhibitor, thus translating basic structural biology principles to new therapeutic modalities.
Structures of large protein-nucleic acid assemblies implicated in DNA repair, ATP-driven long-range diffusion by ATP motors in maintenance of genome integrity, early embryonic development and drug discovery.
Rising STARs Award
Funding Agency University of Texas (UT) System
Period 2017 – 2020
Role Principal Investigator
|Year||Name of Honor/Prize||Awarding Organization|
|2017||Rising STARs Award||University of Texas (UT) System|
|2012||Outstanding poster award||NYSBDG meeting at Weill Cornell Medical School, New York, NY|
|2008||Charles H. Revson Senior Fellowship in Biomed. Sciences||Mount Sinai School of Medicine Nominee|
|2007||Poster competition - 1st Place||Mount Sinai School of Medicine, New York, NY|
|2004||Research fellowship||Ministry of Education, Italy|
|2003||Research Fellowship during International Ph.D. program||CIRMMP, Florence, Italy|
|2001||VSRP Fellowship||Tata Institute of Fundamental Research, Mumbai, India|
|2000||Postgraduate fellowship during M.Tech program||Department of Biotechnology, Government of India|
|1991||National Scholarship||Government of India|
Rechkoblit O.,* Gupta Y.K.,* Malik R.,* Rajashankar K.R., Johnson R.E., Prakash L., Prakash S., Aggarwal A.K. Structure and mechanism of human PrimPol, a DNA polymerase with primase activity. Science Advances 2016 Oct 21;2: e1601317. * Co-first author
Divakar S., Vasquez R., Dutta K., Baker S.J., Cosenza S.C., Basu I., Gupta Y.K., Reddy M.V., Ueno L., Hart J.R., Vogt P.K., Mullholland D., Guha C., Aggarwal A.K., Reddy E.P.. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell 2016 Apr 21;165(3):643-655.*
* Highlighted by Nature Reviews Drug Discovery 2016 June 1 (15):381, Cancer Discovery 2016 June 2 (6):573
Callahan S.J., Luyten Y.A., Gupta Y.K., Morgan R.D., Wilson G.G., Roberts R.J., Aggarwal A.K. Crystal structure of type IIL restriction-modification enzyme MmeI in complex with DNA: implications for engineering of new specificities. PLoS Biology 2016 Apr 15;14(4):e1002442.
Gupta Y.K., Chan S.H., Xu S.Y., Aggarwal A.K. Structural basis of asymmetric DNA methylation and ATP-triggered long-range diffusion by EcoP15I. Nature Communications 2015 Jun 6:7363.
Thompson R., Shah R.B., Liu P.H., Gupta Y.K., Ando K., Aggarwal A.K., Sidi S. (2015) An inhibitor of PIDDosome formation. Mol Cell 2015 Jun 4;58(5): 767-79.
He X., Hull V., Gidwani S., Fu X., Gupta Y.K., Thomas J.A., Black L.W., Xu S.Y. Expression and purification of a single-chain Type IV restriction enzyme Eco94GmrSD and determination of its substrate preference. Sci. Rep. 2015 May 19;5:9747.
Chen X., Ali Khajeh J., Ju J.H., Gupta Y.K., Stanley C.B., Do C., Heller W.T., Aggarwal A.K., Callaway D.J.E., Bu Z. (2015) Phospatidylinositol 4,5-bisphosphate clusters the cell adhesion molecule CD44 and assmebles a specific CD44-Ezrin hetero complex, as revealed by small angle neutron scattering. J. Biol. Chem. 2015 Mar 6;290(10):6639-52.
Stachnik A., Yuen T., Iqbal J., Sgobba M., Gupta Y., Lu P., Colaianni G., Ji Y.(13 authors), Buettner C., Bian Z., Zallone A., Aggarwal A., Haider S., New M., Sun L., Narla G., Zaidi M. Repurposing of bisphosphonates for the prevention and therapy of non-small cell lung cancer. Proc Natl Acad Sci USA 2014 Dec 16; 111:17995-18000.
Yuen T., Stachnik A., Iqbal J., Sgobba M., Gupta Y., Lu P., Colaianni G., Ji Y., (12 authors), Davies T., Bian Z., Zallone A., Aggarwal A., Haider S., New M., Sun L., Narla G., Zaidi M. Bisphosphonates inactivate human EGFRs to exert anti-tumor actions. Proc Natl Acad Sci USA 2014 Dec16; 111:17989-17994.
Mujtaba S., Winer B.Y., Jaganathan A., Patel J., Sgobba M., Schuch R., Gupta Y.K., Haider S, Wang R, Fischetti VA. Anthrax SET protein: a potential virulence determinant that epigenetically represses NF-κB activation in infected macrophages. J. Biol. Chem. 2013 Aug 9;288(32):23458-72.
Xu SY, Gupta Y.K. Natural zinc ribbon HNH endonucleases and engineered zinc finger nicking endonuclease. Nucleic Acids Res. 2013 Jan 1;41(1):378-90.
Gupta Y.K., Yang L., Chan S.H., Samuelson J.C., Xu S.Y., Aggarwal A.K. Structural insights into the assembly and shape of Type III restriction-modification (R-M) EcoP15I complex by small angle x-ray scattering. J. Mol Biol. 2012 Jul ;420(4-5):261-8.
Xu S.Y., Nugent R.L., Kasamkattil J., Fomenkov A., Gupta Y., Aggarwal A., Wang X., Li Z., Zheng Y., Morgan R. Characterization of Type II and III restriction-modification systems from Bacillus cereus strains ATCC10987 and ATCC14579. J. Bacteriol. 2012 Jan;194(1):49-60.
Gupta Y.K., Lee T.H., Edwards T.A., Escalante C.R., Kadyrova L.Y., Wharton R.P., Aggarwal A.K. Co-occupancy of two Pumilio molecules on a single hunchback NRE. RNA 2009 Jun;15:1029-35.
Gupta Y.K., Nair D.T., Wharton R.P., Aggarwal A.K. Structures of human pumilio with noncognate RNAs reveal molecular mechanisms for binding promiscuity. Structure 2008 Apr;16, 549-557 (PMID 18328718)* *Featured as journal cover article, RNA Apr 2009: 15 (4)
Bertini, I., Gupta, Y.K., Luchinat, C, Parigi, G., Peana, M., Sgheri L., Yuan J. Paramagnetism-based NMR restraints provide maximum allowed probabilities for the different conformations of partially independent protein domains. J. Am. Chem. Soc. 2007 Oct 24;129(42):12786-12794.
Edwards, T.A., Butterwick, J.A., Zeng, L., Gupta, Y.K., Wang, X., Wharton, R.P., Palmer III, A.G., Aggarwal, A.K. Solution structure of the Vts1 SAM domain in the presence of RNA. J. Mol. Biol. 2006 Mar 10;356(5):1065-72.
Bertini, I., Gupta Y.K., Luchinat, C., Parigi, G., Schlörb C., Schwalbe H. NMR Spectroscopic detection of protein protons and longitudinal relaxation rates between 0.01 and 50 MHz. Angew. Chem. Int. Ed., 2005 Apr 8;44 (15), 2223-5.
Baig, I., Bertini, I., Del Bianco, C., Gupta, Y.K., Lee, Y.M., Luchinat, C., Quattrone, A. Paramagnetism-based refinement strategy for the solution structure of human α-Parvalbumin. Biochemistry 2004 May 11;43 (18), 5562 –5573.
Gupta Y.K. is a primary author in publications # 16, 18 & 19 but authors were alphabetically ordered by their surnames as per institutional rule in these three (3) publications.
Dr. Gupta is a recipient of the UT Rising STARs Award