HIV Clinical Care; General Infectious Diseases
Pharmacology; Drug Discovery
Our laboratory broadly focuses on DNA modifying enzymes and pathways, particularly those that contribute to genomic plasticity. We utilize a broad array of approaches, including biochemical characterization of enzyme mechanisms, chemical synthesis of enzyme probes, and biological assays spanning immunology and virology to study the fundamental question of how a genomic diversity arises in nature.
Mutation and modification of the genome play an important role in several physiologically relevant areas and our areas of interest include:
1. Decipher the molecular basis for deamination by AID/APOBEC enzymes and perturb deaminase immunological functions
From the host immune perspective, the generation of genomic diversity is used as both a defensive and an offensive weapon. Host mutator enzymes such as Activation-Induced Cytidine Deaminase (AID) seed diversity in the adaptive immune system by introducing targeted mutations into the immunoglobulin locus that result in antibody maturation. Related deaminases of the innate immune system can directly attack retroviral threats by garbling the pathogen genome through mutation, as accomplished by the deaminase APOBEC3G, which restricts infection with HIV. Immune mutator enzymes, however, also pose a risk to the host, as overexpression or dysregulation have been associated with oncogenesis.
2. Explore the interplay of cytosine modifying enzymes on DNA demethylation
The singular genome is responsible for a wealth of different cell types, each of which can respond and adapt to environmental cues. In part, these epigenetic differences are linked to DNA modification. These modifications center around cytosine, where DNA deamination (AID/APOBEC enzymes) , oxidation (TET family enzymes) and methylation (DNMTs) can all interplay and tune the genome's potential. We are interested in the enzymatic activities of these cytosine modifying enzymes, particularly in the process of DNA demethylation which plays a role in embryogenesis, gene regulation and a potential pathological role in cancer.
3. Target pathogen pathways that promote evolution and resistance.
From the pathogen perspective, alteration in key antigenic determinants at a rate that outpaces immune responses is a potent means for evasion. Further, rapid mutation may allow for the development of resistance to antimicrobials. In bacteria, adaptation and evolution are closely linked to the stress response of SOS pathway. The SOS pathway can be triggered by numerous stressors, including antibiotics, and the net result is accelerated acquisition of drug resistance. We aim to characterize the key regulatory and effector enzymes from the SOS pathway and to target the pathway as a means to combat antibiotic resistance.
Our research program aims to understand these pathways of purposeful DNA modification and mutation. Additionally, we apply chemical biology to decipher and target these pathways, to impede the development of multidrug-resistance in pathogens or prevent the neoplastic transformations that can result from genomic mutation.
Nabel CS, Schutsky EK, Kohli RM.: Molecular targeting of mutagenic AID and APOBEC deaminases.
Cell Cycle 13(2), 2014.
Nabel CS, Lee JW, Wang LC, Kohli RM: Nucleic acid determinants for selective deamination of DNA over RNA by activation-induced deaminase. Proc Natl Acad Sci USA 110(35): 14225-30, 2013.
Kohli RM, Zhang Y: TET enzymes, TDG and the Dynamics of DNA Demethylation. Nature 502: 472-9, 2013.
Nabel CS, Manning SA, Kohli RM: The Curious Chemical Biology of Cytosine: Deamination, Methylation and Oxidation as Modulators of Genomic Potential. ACS Chemical Biology 7(1): 20-30, 2012.
Nabel CS, Jia H, Ye Y, Shen L, Goldschmidt HL, Stivers JT, Zhang Y, Kohli RM.: AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nature Chem Biol 8(9): 751-758, 2012.
Nabel CS, Kohli RM: Demystifying DNA Demethylation. Science 333: 1229-1230, 2011.
Kohli RM, Maul RW, Guminski AF, McClure RL, Gajula KS, Saribasak H, McMahon MA, Siliciano RF, Gearhart PJ, Stivers JT.: Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. J Biol Chem 285(52): 40956-40964, 2010.
Kohli RM: The Chemistry of a Dynamic Genome. Nature Chem Biol 6(12): 866-868, 2010.
Kohli RM, Burke MD, Tao J, Walsh CT: Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules. J Am Chem Soc 125: 7160-7161, 2003.
Kohli RM, Walsh CT, Burkart MD: Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418: 658-661, 2002.
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Last updated: 09/04/2014
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