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Profile of Dinshaw J. Patel PROFILE PROFILE Profile of Dinshaw J. Patel Tinsley H. Davis Science Writer Small-noncoding RNA molecules are the “It was clear to me that the excitement in re- dark matter of molecular biology. From small search had shifted to the life sciences,” he says. interfering (si) RNAs that silence invading Switching fields, Patel performed his first pathogens to microRNAs that fine-tune gene postdoctoral training with biochemist Robert expression, noncoding RNAs carry out a vast Chambers at New York University School of number of functions within the cell. “It was Medicine, studying transfer RNA molecules. generally believed in the early days of molec- Meanwhile, a former colleague from Caltech, ular biology that RNA was just a passive Angelo Lamola, had moved to AT&T Bell Dinshaw J. Patel. Image courtesy of Memorial intermediate on the pathway from DNA to Laboratories (Bell Labs) in Murray Hill, New Sloan Kettering Cancer Center. protein, but noncoding RNA architecture Jerseyand,in1968,invitedPateltojoinhis and its interactions with partners is much biophysics group as a postdoc. Patel recalls more intricate and interesting,” says struc- that Lamola and the set-up at Bell Labs, with academic jobs, eventually taking a position at tural biologist Dinshaw J. Patel. Elected to only one scientist and one technician per Columbia University Medical School in 1984 the National Academy of Sciences in 2009, laboratory, provided independence and fos- as a Professor in the Biochemistry and Mo- Patel has spent his career deciphering the tered creativity. Soon, Patel had published lecular Biophysics Department. “The envi- shapes of biomolecules and principles under- several single-author papers on isomeriza- ronment changed dramatically,” he recalls. lying molecular complex formation. In his tions in retinal, the chromophore that binds Patel now had responsibility for building a Inaugural Article, Patel, the Abby Rockefeller to rhodopsin in the eye (3). laboratory group, raising grant funds, and Mauzé Chair in Experimental Therapeutics at Two years later, Frank Bovey, head of Bell lecturing students. He began to study the the Memorial Sloan Kettering Cancer Center, Lab’s polymer chemistry division, offered structure of DNA duplexes containing helical explores how the PAZ-binding domain of Patel a permanent position. Patel began using errors, such as mismatches and bulges, and PIWI proteins forms a pocket capable of NMR to study the conformations of biolog- chemical modifications, as well as drug–DNA binding the 3′-ends of piRNAs, noncoding ically active peptides, heme proteins, and complexes that target the double helix. RNA molecules that help maintain the integ- transfer RNAs by monitoring stable ex- In 1992, Patel moved to his current aca- rity of germ-line DNA (1). changeable protons that served as unique demic home at the Memorial Sloan Kettering markers in spectral regions devoid of other Cancer Center, where he says, together with America Beckons “ resonances. NMR was in its infancy in those biochemist James Rothman, he developed the PatelwasborninMumbai,Indiain1942and days, so individuals were focused on de- grew up in the Zoroastrian community. His structural biology program. Patel notes that veloping simple approaches to monitor bio- themoveresultedinsizeablelong-termin- father was a civil engineer, and in an ed- polymer folds, interactions, and structural ucation-rich setting, Patel immersed him- stitutional resources to initiate challenging transitions,” he says, and notes that his “ self in the sciences. “Because India was a projects. SloanKetteringwasonanupward structural and hydrogen exchange studies trajectory under the visionary leadership of developing country, science was what we identified a dinucleotide repeat adopted by Paul Marks,” says Patel, noting that he did learned in textbooks, with minimal practical d(G-C) repeats (4), providing early insights ” n not realize then how special the scientific experience, Patel explains. Drawn to the into the topology of left-handed Z-DNA environment was, with the Rockefeller Uni- United States, at the age of 19 Patel enrolled identified eventually in the Alexander Rich versity and Weill Cornell Medical College just in graduate school at the California Institute group at MIT. By 1983, Patel had earned the of Technology (Caltech). In the laboratory of Bell Laboratories Distinguished Member of across the street. Jack Roberts, Patel got his first experience Technical Staff Award. “In some ways, it Patel explains that collaborations with the working with NMR spectroscopy, a tool to was sort of an awkward thing to be Rockefeller University faculty, including mo- visualize molecular structure that would figure working in the life sciences at a telephone lecular and cell biologists Thomas Tuschl, “ prominently in his early career. The creativity companyandbeinghandsomelyrewarded DavidAllis,RobertRoeder,andPaulGreen- “ and intensity of the scientific environment at for it” Patel says, and refers to his 17 years at gard, have been key to his growth. Structural ” ” “ Caltech shaped his future scientific career, Bell Labs as a “transforming period,” gener- biology is powerful, he says, because it Patel says. ating “enthusiasm and hunger for curiosity- precisely defines the positions of atoms in ’ After receiving his Master sdegreein1963 driven discovery.” proteins, nucleic acids, and their complexes.” for research on ring opening rearrangements Importantly, structural insights can allow the in small ring cyclopropane compounds (2), Easing into Academia design of very specific, targeted mutations, Patel moved to New York University to work Eventually, as Bell Labs was breaking up, with photochemist David Schuster. Three Patel explains, “I could see the writing on the This is a Profile of a recently elected member of the National years later, after graduating with a doctorate in wall, especially for someone doing research Academy of Sciences to accompany the member’s Inaugural Article Chemistry, Patel found himself at a crossroads. in the life sciences.” He began to apply for on page 903 in issue 3 of volume 108. www.pnas.org/cgi/doi/10.1073/pnas.1512793112 PNAS Early Edition | 1of3 Downloaded by guest on September 29, 2021 senses this,” explains Patel. An enzyme known as Dicer chops the invading RNA into short segments,termedsiRNA.Onestrandofthe siRNA, the guide strand, is used like a fishing lure and fed into a molecular complex that seeks out and degrades complementary viral messenger RNAs, preventing viral protein production. Patel focused his research on Dicer and another nuclease, Argonaute (Ago), which play key roles in RNA interference. In collaboration with molecular biologist Thomas Tuschl, Patel solved the structure of a binary prokaryotic Ago complex, which showed the trajectory of the bound guide strand anchored at both its ends and the accessibility of the appropriate segment for Crystal structures of Thermus thermophilus Argonaute (labeled and color-coded by domains) with recognition of the target RNA (10). He next bound 5′-phosphorylated guide DNA (in red) as a binary complex (A) and with target RNA (in solved structures of the ternary Ago com- blue) as a ternary complex in B. Reprinted with permission from Macmillan Publishers Ltd., ref. 5. plexes bound to RNA targets, revealing insights into how the target strand is ul- timately cleaved (11). Patel later studied allowing an understanding of how selective in his research program. He expanded the eukaryotic versions of Ago and Dicer perturbations affect biological function. his toolkit into X-ray crystallography to in budding yeast with biologist David Patel continued to explore his interest get higher-resolution and timely views of Bartel, finding that, unlike its prokaryotic in higher-order DNA architecture. DNA structures of molecular complexes, and counterparts, Dicer in budding yeast starts typically occurs in double-stranded—or he decided to study RNA, which can fold cleaving in the interior of the invading duplex—form. Patel investigated the NMR- in unique and surprising ways. Patel fo- RNA and works outward (12). based structures of DNA triplexes and cused his structural RNA research on ribo- Viruses counterattack degradation of their quadruplexes, identifying the role of base- switches, ribozymes, and RNA interference. RNAs by evolving protein suppressors that triplet- and tetrad-pairing alignments, as well Riboswitches are noncoding sections of target various steps of the RNA interference as strand directionality and turn motifs, in messenger RNAs that contain a sensing do- pathway. Patel established how the viral defining the structural scaffolds that multi- main that binds small ligands, such as me- suppressor p19 forms a homodimer and uses stranded DNA forms. The work also illumi- tabolites. Binding of a specific ligand changes a caliper-like mechanism to target siRNA nated the diversity of G-quadruplex folds the conformation of the RNA, allowing it to (13). Recounting this phase of his career, adopted by regions of guanine-rich DNA, function as an on-off switch for gene ex- Patel says, “There were several once-in-a- such as those found in oncogenic promoters pression related to the ligand’s concentration. decade moments linked to discoveries of and telomeres (6). Patel’s work on riboswitches defined a range novel folds and interaction principles in our During his first decade at Memorial Sloan of higher-order RNA architectures, ligand studies of RNA interference, where molec- 2+ Kettering, Patel also investigated
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