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Research Spending & Results

Award Detail

Awardee:UNIVERSITY OF UTAH, THE
Doing Business As Name:University of Utah
PD/PI:
  • Cynthia J Burrows
  • (801) 585-7290
  • burrows@chem.utah.edu
Award Date:01/30/2012
Estimated Total Award Amount: $ 488,000
Funds Obligated to Date: $ 488,000
  • FY 2012=$488,000
Start Date:04/01/2012
End Date:03/31/2016
Transaction Type:Grant
Agency:NSF
Awarding Agency Code:4900
Funding Agency Code:4900
CFDA Number:47.049
Primary Program Source:040100 NSF RESEARCH & RELATED ACTIVIT
Award Title or Description:Redox Photochemistry of Oxidized Bases in DNA and RNA
Federal Award ID Number:1152533
DUNS ID:009095365
Parent DUNS ID:009095365
Program:Chemistry of Life Processes
Program Officer:
  • David Rockcliffe
  • (703) 292-7123
  • drockcli@nsf.gov

Awardee Location

Street:75 S 2000 E
City:SALT LAKE CITY
State:UT
ZIP:84112-8930
County:Salt Lake City
Country:US
Awardee Cong. District:02

Primary Place of Performance

Organization Name:University of Utah
Street:315 S 1400 East
City:Salt Lake City
State:UT
ZIP:84112-0850
County:Salt Lake City
Country:US
Cong. District:02

Abstract at Time of Award

With this award, the Chemistry of Life Processes Program is supporting the research of Professor Cynthia Burrows of the University of Utah. Professor Burrows hypothesizes that simple chemical transformations of RNA bases could have been the key steps in creating redox active catalysts driving early chemical systems toward a primitive metabolism. With prior NSF funding, her laboratory has shown that the oxidized base 8-oxoguanine serves as a photochemical catalyst to reductively reverse cyclobutane pyrimidine dimers to monomers. In this reaction, 8-oxoguanine acts as a flavin mimic to facilitate excited state electron transfer. Future work will explore 8-oxopurines and other redox active RNA purine and pyrimidine base derivatives for their ability to mediate oxidation and reduction reactions. For example, key reactions of early Earth must have included the ability to interconvert alcohols and aldehydes or ketones (e.g. lactate/pyruvate) using redox cofactors analogous to NADH and FADH2. Reactions such as these will be studied in RNA world-like conditions in order to test the hypothesis that simpler versions of these RNA-based cofactors could have presaged modern-day metabolism. The broader impacts of this project are demonstrated in the unusual link between DNA damage and repair chemistry pertinent to cancer and the chemistry of primordial Earth. Photoinduced electron transfer appears to play a role in both realms, and insights from this work could be broadly applicable to other disciplines. Students trained on the project will be involved in interdisciplinary sciences including aspects of synthetic and physical organic, analytical and biochemistry. Professor Burrows has demonstrated continuing leadership in broadening participation, including programs that advance the careers of women scientists, and will continue to be active in dissemination of research to public audiences.

Publications Produced as a Result of this Research

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Khiem Van Nguyen; Burrows, Cynthia J. "Whence Flavins? Redox-Active Ribonucleotides Link Metabolism and Genome Repair to the RNA World" ACCOUNTS OF CHEMICAL RESEARCH, v.45, 2012, p.2151-2159.

Y. Zhang, J. Dood, A. Beckstead, J. Chen, X.-B. Li, C. J. Burrows, Z. Lu, S. Matsika, and B. Kohler "Ultrafast Excited-State Dynamics and Vibrational Cooling of 8-oxo-7,8-dihydro-2?-deoxyguanosine in D2O" J. Phys. Chem. A, v.117, 2013, p.12851. doi:10.1021/jp4095529 

Y. Zhang, J. Dood, A. Beckstead, X.-B. Li, K. V. Nguyen, C. J. Burrows, R. Improta, and B. Kohler "Ultrafast IR spectroscopy and DFT calculations reveal efficient UV-induced charge separation and recombination in a DNA dinucleotide" Proc. Natl. Acad. Sci. USA, v.111, 2014, p.11612. doi:10.1073/pnas.1404411111 

Khiem Van Nguyen; Burrows, Cynthia J. "Photorepair of cyclobutane pyrimidine dimers by 8-oxopurine nucleosides" JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, v.25, 2012, p.574-577.

Khiem Van Nguyen; Burrows, Cynthia J. "A prebiotic role for 8-oxo-7,8-dihydroguanosine as a flavin mimic in pyrimidine dimer repair" Journal of the American Chemical Society, v.133, 2011, p.14586?145. doi:10.1021/ja207225 


Project Outcomes Report

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Research conducted in this study was aimed at understanding the interaction of the genetic molecule DNA with light.  While ultraviolet light is generally considered deleterious to DNA through the formation of thymine dimers, we hypothesized that certain modified components of DNA, namely bases like guanine (G) that had undergone free radical oxidation, could be beneficial and actually lead to the repair of photo-induced damage to DNA.  We noted that vitamin B2, riboflavin, is structurally similar to the base guanine, and shares chemical properties in common with the oxidized base 8-oxoguanine (OG). Indeed, using a wavelength of light longer than that originally used to inflict damage on DNA (in the form of thymine dimers, a molecular promoter of skin cancer) led to electron transfer between OG and a thymine dimer such that the dimer reverted back to the original form of DNA.

The broader impact of these studies is that we have a deeper picture of how light can cause both damage and repair to the bases of DNA.  Additionally, we see that a simple change in a DNA or RNA base gives it properties similar to ribonucleotide vitamin.  Several of the vitamins like riboflavin are small dinucleotide components based on RNA that are thought to be "fossils of the RNA World," i.e. remnants of an earlier pre-biotic life in which these small heterocycles were responsible for both the genetics and catalytic functions leading to simple organisms.  Thus, these studies provide insight into the molecular basis for the emergence of life.

The research was conducted principally by graduate students who are now trained in DNA and RNA chemistry techniques, how to evaluate data, how to prepare scientific reports, and how to present their work to a critical audience.  These students have gone on to jobs in both education and biotech industries.  The PI presents lectures on this work in many contexts including to the public as part of her role as co-director of the Curie Club, engaging women students and faculty in science, at the University of Utah.


Last Modified: 05/29/2016
Modified by: Cynthia J Burrows

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