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Home > Faculty > SUSTech Faculty Finder > Dinshaw J.Patel

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Dinshaw J.Patel


Chair Professor

Department of Biology

0755-88018446

pateld@mskcc.org

Self-introduction:
I received my PhD in Chemistry from New York University (NYU) in 1968 for research in the photochemistry. I decided next to shift the emphasis of my research to the life sciences and hence completed postdoctoral training (one year) in Biochemistry at NYU School of Medicine followed by postdoctoral training (two years) in Biophysics at AT&T Bell Laboratories. I was next promoted to permanent Member of Technical Staff at Bell Labs and spent the next 15 years undertaking NMR-based studies of the structure and dynamics of cyclic peptides, proteins and nucleic acids. I moved to Columbia University Medical School in 2004 as a tenured Professor of Biochemistry and Molecular Biophysics where my group spent the next 8 years doing NMR-based research on DNA mismatches, bulges and junctions, on DNA triplexes and G-quadruplexes, and drug-DNA complexes. I was recruited in 1992 as a tenured Member to the Cellular Biochemistry and Biophysics Program at the Memorial Sloan-Kettering Cancer Center to set up a Structural Biology component to the program. My group’s research during the 1990s focused on NMR-based studies of covalent chiral carcinogen-DNA adducts, and complexes of antibiotics and peptides with natural and in vitro selected RNA targets.
My laboratory began to increasingly use x-ray crystallography starting around 2000 with the emphasis initially on RNA-mediated gene regulation. My group determined the higher order architectures of compact riboswitch sensing domains bound to amino acids, metabolites and ions, as well as elucidated how RNA containing only four nucleotides could generate pockets capable of recognizing specific ligands and discriminating against closely-related analogs. In the RNA silencing area, my group made fundamental discoveries over the next decade related to the structural biology of eubacterial Argonaute proteins and their complexes with guide DNA and target RNAs, thereby providing mechanistic insights into the nucleation, propagation and cleavage steps of Ago-mediated cleavage of mRNA. More recently, my group extended its research to Dicer proteins where we identified an inside-out non-canonical pathway of dsRNA cleavage by budding yeast Dicer, in contrast with to an outside-in pathway for Dicer’s cleavage activity in higher eukaryotes. My group’s efforts also focused on structure determination of disease-related protein-RNA complexes, thereby defining the principles underlying the specificity of intermolecular recognition and the role of protein dimerization in facilitating complex formation. 
In 2005 my group initiated a comprehensive research program in epigenetic regulation focused on understanding the diversity of mechanisms for site- and state-specific readout of histone marks by writer, reader and eraser protein modules. Initial efforts with single effector modules were expanded over time to multivalent readout at the histone peptide and nucleosomal level. These studies were extended to the identification of small molecules that targeted effector pockets with high affinity and specificity, and elucidation of the role of histone chaperones and chromatin remodelers in epigenetic regulation. My group initiated our research on DNA methylation mark-mediated epigenetic regulation in 2010 by focusing our structural studies on a pair of DNMT1-DNA complexes, whereby we established how a combination of autoinhibitory and productive mechanisms ensured the high fidelity of DNMT1-mediated maintenance DNA methylation. This research was next extended to studies that provided mechanistic insights into plant proteins that mediate the role of polymerases pol-IV and pol-V in RNA-directed DNA methylation in A. thaliana.
My group initiated a structural biology program in 2003 on lipid transfer proteins that acquire and release neutral glycosphingolpids and charged phosphosphingolipids during lipid intermembrane transfer and presentation processes. Our studies established the molecular basis underlying differentiation of neutral from charged lipids by their respective head group recognition centers, and defined the alignment of one or both lipid chains within a molded-to-fit hydrophobic tunnel, thereby supporting a cleft-like gating mechanism, whereby lipid chains sequentially entered and departed the tunnel in the membrane-associated state. 
More recently, my group has turned its attention to the field of pattern recognition receptors that sense double-stranded nucleic acids in the cytosol, thereby triggering a cascade of events that activate the innate immune response. Our efforts have focused on cGAS, the metazoan sensor of cytosolic dsDNA, the second messenger cGAMP and the adaptor STING. Our structural studies identified cGAMP, produced by DNA-activated cGAS from GTP and ATP, to be c[G(2’,5’)pA(3’,5’)p], that contained an unanticipated 2’,5’ linkage at the GpA step. Our research was next extended to STING activation by cGAMP and targeting by the anti-viral agent DMXAA. 

 

Professional Experience:
1967       New York Univ. Medical School New York, NY. Biochemistry.
1968 - 1969       AT&T Bell Laboratories, Murray Hill, NJ. Biophysics.
1970 - 1984       Member of Technical Staff, Polymer Chemistry Department, 
AT&T Bell Laboratories, Murray Hill, NJ
1984 - 1992       Professor of Biochemistry & Molecular Biophysics, 
College of Physicians & Surgeons, Columbia University, New York, NY
1992 -       Member, Structural Biology Program
Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York
1994 -Professor, Graduate Program in Biochemistry & Structural Biology,
Weill School of Medical Sciences, Cornell University, New York, NY


Educational Background:
1961B.Sc. University of Mumbai, Mumbai, India. Chemistry
1963M.S. California Institute of Technology, Pasadena, CA. Chemistry
1968PhD. New York University, New York, NY. Chemistry


Honors & Awards:
1961 - 1963       Jamshetjee N. Tata Fellow
1983       AT&T Bell Laboratories Distinguished Technical Staff Award
1992 -       Abby Rockefeller Mauzé Chair in Experimental Therapeutics (MSKCC)
1997       Distinguished Alumnus Award, New York University
1997 - 1999       Harvey Society (Vice-President 97-98; President 98-99)
2013       NIH Directors Transformative R01 Award (with Thomas Tuschl and Uwe Ohler)
2009       Member, National Academy of Sciences, USA
2014       American Academy of Arts and Sciences, USA


Selected Publication:
1.Du, J., Johnson, L. M., Jacobsen, S. E. and Patel, D. J. (2015). DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell Biol. 16, 519-532.
2.Noh, K. M., Wang, H., Kim, H. R., Wenderski, W., Fang, F., Li, C., Dewell, S., Ferris, A., Hughes, S. H., Zheng, D., Melnick, A, Patel, D. J., Li, H. and Allis, C. D. (2015). Engineering of a histone recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs. Mol. Cell 59, 89-103.
3.Webster, A., Li, S., Hur, J. K., Wachsmuth, M., Bois, J., Perkins, E. M., Patel, D. J. and Aravin, A. A. (2015). Aub and Ago3 are recruited to nuage through two mechanisms to form a ping-pong complex assembled by Krimper. Mol. Cell 59, 564-575.
4.Chen, S., Ze, Y., Wilkinson, A., Deshpande, A. J., Sidoli, S., Krajewski, K., Strahl, B. D., Garcia, B. A., Armstrong, S. A., Patel, D. J. and Gozani, O. (2015). The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-methylation at H3K79. Mol. Cell 60, 319-327.
5.Huang, H., Stromme, C. B., Saredi, G., Hodl, M., Strandsby, A., Strandsby, A., Gonzalez-Aguilera, C., Chen, S., Groth, A. and Patel, D. J. (2015). A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks. Nat. Struct. Mol. Biol. 22, 618-626.
6.Dai, Q., Ren, A., Westholm J. O., Patel, D. J. and Lai, E. (2015). Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family. Genes Dev.29, 48-62.
7.Chen, S., Ruflange, A., Huang, H., Nourani, A. and Patel, D. J. (2015). Structural basis of histone H3/H4 tetramer maintenance during transcription by chaperone Spt2. Genes Dev.29, 1326-1340.
8.Murn, J., Zarnack, K., Yang, Y. J., Durak, O., Murphy, E. A., Cheloufi, S., Gonzalez, D. M., Teplova, M., Curk, T., Zuber, J., Patel D. J., Ule, J., Luscombe, N. M., Tsai, L. H., Walsh, C. A. and Shi, Y. (2015). Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt. Genes Dev. 29, 501-512.
9.Ren, A., Wang, X. C., Kellenberger, C. A., Rajashankar, K. R., Jones, R., Hammond, M. C. and Patel, D. J. (2015). Structural basis for molecular discrimination by a 3’,3’-cGAMP riboswitch. Cell Reports 11, 1-12.
10.Ren, A., Xue, Y., Peselis, A., Serganov, A., Al-Hashimi, H. and Patel, D. J. (2015). Structuraland Dynamic Basis for Low-Affinity, High-Selectivity Binding of L-Glutamine by the Glutamine Riboswitch. Cell Reports 13, 1800-1813.
11.Vasilyev, N., Polonskaia, A., Darnell, J. C., Darnell, R. B., Patel, D. J. and Serganov, A. (2015). Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP. Proc. Natl. Acad. Scis. USA. 112, E5391-E5400.
12.Kosutic, M., Neuner, S., Ren, A., Flur, S., Wunderlich, C., Mayrhofer, E., Vusurovic, N., Seikowski, J., Westhof, E., Hobartner, C., Patel, D. J., Kreitz, C. and Micure, R. (2015). A Mini-Twister Variant and Impact of Residues/Cations on the Phosphodiester Cleavage of this Ribozyme Class. Angew. Chemie Int. Edn. 54, 15128-15133.
13.Malinina, L., Simanshu, D. K., Zhai, X., Samygina, V. R., Kamlekar, R., Kenoth, R., Ochoa-Lizarralde, B., Molotkovsky, J. G., Patel, D. J. and Brown, R. E. (2015). Sphingolipid transfer proteins defined by the GLTP-fold. Quart. Rev. Biophys. 48, 281-322.
14.Johnson, L. M., Du, J., Hale, C. J., Bischof, S., Feng, S., Chodavarapu, R. K., Zhong, X., Marson, G., Pellergrini, M., Segal, D. J., Patel, D. J. and Jacobsen, S. E. (2014). SRA- and SET-domain-containing proteins link RNA polymerase V occupancy to DNA methylation.Nature 507, 124-128.
15.Swarts, D. C., Jore, M. M., Westra, E. R., Zhu, Y., Janssen, J. H., Snijders, A. P., Wang, Y., Patel, D. J., Berenguer, J., Brouns, S. J. and van der Oost, J. (2014). DNA-guided DNA interference by prokaryotic Argonaute. Nature 507, 258-261.
16.Zhong, X., Du, J., Hale, C. J., Gallego-Bartolome, J., Feng, S., Vashisht, A. A., Chory, J., Wohlschlegel, J. A., Patel, D. J. and Jacobsen, S. E. (2014). Molecular mechanism of action of plant DRM de novo DNA methyltransferases. Cell 157, 1050-1060.
17.Lim, J., Ha, M., Chang, H., Kwon, S. C., Simanshu, D. K., Patel, D. J. and Kim, V. N. (2015). Uridylation by TUT4 and TUT7 marks mRNA for degradation. Cell 159, 1365-1376.
18.Stroud, H., Do, T., Du, J., Zhong, X., Feng, S., Johnson, L., Patel, D. J. and Jacobsen, S. E. (2014). Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis. Nat. Struct. Mol. Biol. 21, 64-72.
19.Swarts, D. C., Makarova, K., Wang, Y., Nakanishi, K., Ketting, R. F., Koonin, E. V., Patel, D. J. and van der Oost, J. (2014). The evolutionary journey of Argonaute proteins. Nat. Struct. Mol. Biol. 21, 743-753.
20.Tian, Y., Simanshu, D. K., Ma, J. B., Park, J-E, Heo, I., Kim, V. N. & Patel, D. J. (2014). A phosphate-binding pocket within the platform-PAZ-connector helix cassette of human Dicer. Mol. Cell 53, 606-616.
21.Du, J., Johnson, L. M., Groth, M., Feng, S., Hale, C. J., Li, S., Vashisht, A. A., Gallego-Bartolome, J., Wohlschlegel, J. A., Patel, D. J. and Jacobsen, S. E. (2014). Mechanism of DNA methylation-directed histone methylation by KRYPTONITE. Mol. Cell 55, 495-504.
22.Lee, M., Choi, Y., Kim, K., Jin, H., Lim, J., Nguyen, T. A., Yang, J., Jeong, M., Giraldez, A. J., Yang, H., Patel, D. J. and Kim, V. N. (2015). Adenylation of maternally inherited microRNAs by Wispy. Mol Cell 56, 696-707.
23.Ren, A. and Patel, D. J. (2014). c-di-AMP binds the ydaO riboswitch in two pseudo-symmetry-related pockets. Nat. Chem. Biol. 10, 780-786.
24.Ren, A., Kosutic, M., Rajashankar, K. R., Frener, M., Santner, T., Westhof, E., Micura, R. and Patel, D. J. (2014). In-line alignment and Mg2+ coordination at the cleavage site of the twister ribozyme. Nat. Commun.15: 5534.
25.Oh, Y-S., Gao, P., Lee, K., Ceglia, I., Zhang, X., Ahn, J-H., Chait, B. T., Patel, D. J., Kim, Y. & Greengard, P. (2013). SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 152, 831-843.
26.Shen, J., Xia, Y., Khotskaya, Y. B., Huo, L., Nakanishi, K., Lim, S-O., Du, Y., Wang, Y., Chang, W-C., Chen, C-H., Hsu, J. L., Lam, Y. C., James, B. P., Liu, C-G., Liu, X., Patel, D. J. & Hung, M. C. (2013). EGFR modulates miRNA maturation in response to hypoxia through phosphorylation of Ago2. Nature 497, 383-387.
27.Law, J. A., Du, J., Hale, C. J., Feng, S., Krajewski, K., Strahl, B. D., Patel, D. J. & Jacobsen, S. E. (2013). Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. Nature 498, 385-389.
28.Sun, X-J., Wang, Z., Wang, L., Jiang, Y., Chen, W-Y., Melnick, A., Patel, D. J., Nimer, S. D. & Roeder, R. G. (2013). A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 500, 93-97.
29.Simanshu, D. K., Kamlekar, R. K., Wijesinghe, D. S., Zou, X., Zhai, X., Mishra, S. K., Molotkovsky, J. G., Malinina, L., Hincliffe, E. H., Chalfant, C. E., Brown, R. E. & Patel, D. J. (2013). Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature 500, 463-467.
30.Gao, P., Ascano, M., Wu, Y., Barchet, W., Gaffney, B. L., Zillinger, T., Serganov, A., Jones, R. A., Hartmann, G., Tuschl, T. and Patel, D. J. (2013). Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094-1107.
31.Gao, P., Ascano, M., Zillinger, T., Wang, Y., Dai, P., Serganov, A. A., Gaffney, B. L., Shuman, S., Jones, R., Deng, L., Hartmann, G., Barchet, W., Tuschl, T. and Patel, D.J. (2013). Structure-function analysis of STING activation by c[G(2’,5’)pA(3’,5’)p] and targeting by antiviral DMXAA. Cell 154, 748-762.
32.Song, J., Teplova, M., Ishibe-Murakami, S. & Patel, D. J. (2012). Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335, 709-712.
33.Kuo, A. J., Song, J., Cheung, P., Ishibe-Murakami, S., Yamazoe, S., Chen, J., Patel, D. J. & Gozani, O. (2012). ORC1 BAH domain links dimethylation of H4K20 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484, 115-119.
34.Ren, A., Rajashankar, K. & Patel, D. J. (2012). Fluoride ion encapsulation by Mg2+ and phosphates in a fluoride riboswitch. Nature 486, 85-89.
35.Nakanishi, K., Weinberg, D., Bartel, D. P. & Patel, D. J. (2012). Structure of yeast Argonaute with guide RNA. Nature 486, 368-374.
36.Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Bantscheff, M., Bountra, C., Bridges, A., Che, K., Diallo, H., Eberhard, D., Hutchinson, S., Joberty, G., Jones, E., Katso, R., Leveridge, M., Mosley, J., Rowland, P., Ramirez-Molina, C., Schofield, C. J., Sheppard, R., Smith, J. E., Swales, C., Tanner, R., Thomas, P., Tumber, A., Drewes, G., Oppermann, U., Patel, D. J., Lee, K., & Wilson, W. (2012). A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404-408.
37.Du, J., Zhong, X., Barnatavichute, Y. V., Stroud, H., Feng, S., Caro, E., Vashisht, A. A., Terragni, J., Chin, H. G., Tu, J., Hetzel, J., Wohlschlegel, J. A., Pradhan, S., Patel, D. J. & Jacobsen, S. E. (2012). Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell 151,167-180.
38.Elsasser, S. J., Huang, H., Lewis, P. W., Allis, C. D. & Patel, D. J. (2012). DAXX histone chaperone envelops an H3.3/H4 dimer for H3.3-specific recognition. Nature 491, 560-565.
39.Song, J., Rechkoblit, O., Bestor, T. H. & Patel, D. J. (2011). Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331, 1036-1040.
40.Ruthenburg, A., Li, H., Milne, T., Dou, Y., McGinty, R. K., Yuen, M., Muir, T. W., Patel, D. J. & Allis, C. D. (2011). Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 145, 692-706.
41.Weinberg, D., Nakanishi, K., Patel, D. J. & Bartel, D. P. (2011). The inside-out mechanism of Dicers from budding yeasts. Cell 146, 262-276.
42.Park, J. E., Heo, I., Tian, Y., Shimanshu, D., Chang, H., Jee, D., Patel, D. J. & Kim, V. N. (2011). Human Dicer recognizes the 5’-phosphorylated end of RNA for efficient and accurate cleavage. Nature 475, 201-205.
43.Wang, Z., Song, J., Milne, T. A., Wang, G. G., Li, H., Allis, C. D. & Patel, D. J. (2010). Pro isomerization in MLL1 PHD3-Bromo cassette connects H3K4me3 readout to CyP33 and HDAC-mediated repression. Cell 141, 1183-1194.
44.Tsai, W-W., Wang, Z., Yiu, T. T., Akdemir, K. C., Xia, W., Winter, S., Tsai, C-Y., Shi, X., Schwarzer, D., Plunkett, W., Aronow, B., Gozani, O., Fischle, W., Hung, M. C., Patel, D. J. & Barton, M. C. (2010). TRIM24 links recognition of a non-canonical histone signature to breast cancer. Nature 468, 927-932.
45.Wang, Y., Juranek, S., Li, H., Sheng, G., Wardle, G. S., Tuschl, T. Patel, D. J. (2009). Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes. Nature 461, 754-761.
46.Wang, G. G., Song, J., Wang, Z., Dormann, H. L., Casadio, F., Li, H., Luo, J., Patel, D. J. & Allis, C. D. (2009). Haematopoietic malignancies initiated by dysregulation of a chromatin-binding PHD fineger. Nature 459, 847-851.
47.Serganov, A., Huang, L. & Patel, D. J. (2009). Coenzyme recognition and gene regulation by a FMN riboswitch. Nature 458, 233-237.
48.Xiao, A., Li, H., Shechter, D., Ahn, S. H., Fabrizio, L., Erajument-Bromage, H., Murakami-Ishibe, S., Wang, B., Tempst, P., Hofmann, K., Patel, D. J., Elledge, S. J. & Allis, C. D. (2009). WSTF regulates the DNA damage response of H2A.X via a novel tyrosine kinase activity. Nature 457, 57-62.
49.Wang, Y., Li, H., Juranek, S., Sheng, G., Tuschl, T. & Patel, D. J. (2008). Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex. Nature 456, 921-926.
50.Wang, Y., Sheng, G., Juranek, S., Tuschl, T. & Patel, D. J. (2008). Structure of the guide-strand-containing argonaute silencing complex. Nature 456, 209-213.
51.Serganov, A., Huang, L. & Patel, D. J. (2008). Structural insights into ligand binding and gene control by a lysine riboswitch. Nature 455, 1263-1267.

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