Exploration of 3D conformational space occupied by quadruplex DNA and i-motifs
GQ and i-motif structures are promising drug targets for cancer. Due to the high structural diversity of GQs and i-motifs and a limited number of available high-resolution structures, our ability to design potent, selective ligands is hampered. Structural information on the i-motif is extremely scarce; the effect of capping interactions in loops on i-motif stability has barely been explored. To develop structure-selective ligands as drug candidates for cancer intervention, high-resolution structural information is necessary. Driven by this gap in knowledge and inspired by our recent success in solving the structure of Tel22-NMM and THM-NMM complexes, we are in the process of crystallizing: 1) a variety of oncogene promoter quadruplexes in complex with ligands studied in our laboratory; 2) i-motif DNA from oncogene promoters alone and in complex with ligands; 3) repetitive DNA associated in replication stress; 4) DNA repeat from centromeres 2 and 3.
Interaction of G-quadruplex DNA with porphyrins and other ligands
Porphyrins are the best characterized class of GQ ligands. The porphyrin 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) is a strong GQ binder but suffers from only modest selectivity for GQ vs. dsDNA. Our laboratory has demonstrated that another porphyrin, N-methylmesoporphyrin IX (NMM) has excellent selectivity for GQ vs dsDNA. Our interest in NMM was sparked by reports of its biological utility and widespread applications. We have characterized the interactions of NMM with a variety of GQ DNA folds and have determined its crystal structures in complex with human telomeric DNA (Tel22) and a GQ from Tetrahymena thermophile (unpublished). Importantly, we have demonstrated unprecedented preference of NMM for a parallel GQ fold. Thus, NMM provides an excellent platform for investigating the structural and chemical requirements for highly selective GQ binders. Other well-studied and highly selective GQ ligands with excellent anti-cancer activities include PDS, Braco-19, 360A, RHPS4, and PhenDC3. Structural characterization of their binding to GQs will inform the design of improved analogues.
(co-PI) NIH R01 Mitochondrial G-quadruplex structures in health and disease, 2019-20204 (PI: Brett Kaufman)
NIH 1R15 (AREA) Deciphering the structure and dynamics of quadruplex DNA and DNA-ligand complexes; 2017-2020
- Camille and Henry Dreyfus Teacher-Scholar Award, Deciphering the structure and dynamics of quadruplex DNA and DNA-ligand complexes, 2016-2020
- Pennsylvania Department of Health, Formula Health Grant Understanding interactions between porphyrin ligands and G-quadruplex DNA. 01/15 - 12/17
- NSF MRI Acquisition of 400-MHz NMR Spectrometer, 08/13 - 07/16, Co-PI
- Swarthmore College Faculty Research Award Interaction of porphyrin ligands with G-quadruplex DNA. 12/07- 06/16
- Initiative d’Excellence de l’Université de Bordeaux (IdEx Bordeaux) Visiting professor Program. 03/15 - 05/15
- Université de Bordeaux Professeur invite Invited Professor Program. 09/14 - 10/14
I actively collaborate with US and international researchers whose expertise and resources complement the work of my lab and provide extraordinary opportunities for my students. I spent the 2010-11 and 2014-15 academic years on sabbatical in the laboratory of J.-L. Mergny at the European Institute of Chemistry and Biology (IECB) in France, and 2018-2019 sabbatical in the laboratory of J. Plavec (National Slovenian NMR center) and V. Gabelica (IECB). Through these collaborations, five of my students and I learned new biophysical, biological, and structural techniques for characterizing non-canonical DNA structures. I, along with one of my students, also spent a few weeks in the laboratory of B. Chaires learning calorimetric techniques. I have established collaborations with J. Schneekloth from NIH, A. Granzhan from Institute Curie, V. Szalai from NIST and with biologists B. Johnson and E. Brown from the University of Pennsylvania and B. Kaufman from the University of Pittsburgh.
from New York University School of Medicine, visiting Swarthmore to learn
about our lab's biophysical characterization techniques
Dr. Brad Chaires (University of Louisville), and Barrett Powell '18 at
the International Meeting on Quadruplex Nucleic Acids in Prague, June 2017
Joint group meeting with Dr. Eric Brown (far left) from the University of Pennsylvania
Thao Tran (IECB, Bordeaux), F. Brad Johnson (UPenn Med School)
Jack Nicoludis '12 and Liliya Yatsunyk at the Third International Meeting on
G-quadruplex DNA and G-assembly in Italy, Sorrento, July 2011
Most research is our laboratory is done by Swarthmore undergraduates. Students with interest in cancer research, crystallography, synthetic work, biophysical work, interdisciplinary work between chemistry, biology, and physics are highly encouraged to apply. Students from the departments other than Chemistry are also encouraged to apply. Our lab is a home for Engineering, Biology, and Psycology students. Based on background and interests, students will pursue independent projects or be teamed with senior students in the lab. Contact Professor Yatsunyk via e-mail or stop by our lab and talk to students about their experience.