- PROFESSOR Structural and Chemical Biology
- PROFESSOR Pharmacology and Systems Therapeutics
- Antigen Presentation
- Computational Biology
- Computer Simulation
- DNA Repair
- Drug Design and Discovery
- Gene Regulation
- Mathematical and Computational Biology
- Membrane Proteins/Channels
- Post-Transcriptional Processing
- Protein Folding
- Protein Structure/Function
- Theoretical Biophysics
DNA Damage and Repair
The long-term goal of this project is to develop a molecular understanding, derived from a combined theoretical-experimental collaborative approach, of the principles of specific DNA damage recognition and repair. The collaboration is between this laboratory and that of J. B. Alexander Ross.
Two mechanisms of damage repair are important for the maintenance of the genetic material encoded in DNA. One is the excision of the damage followed by a restoration of the correct DNA sequence in a number of coordinated steps represented by the Base Excision Pathway (BER). The other repair process is accomplished by an error-free translesion synthesis. We study the mechanism of damage recognition and its excision by two repair enzymes: Endonuclease V (endoV) recognizes a thymine dimer (TD) and flips the complementary adenine to the 5-thymine of the TD into a protein pocket before hydrolyzing the glycosidic bond of the TD. Uracil DNA Glycosylase (UDG) recognizes uracil in DNA, flips it into a specific pocket and hydrolyzes the glycosidic bond. It appears that the mechanism of base flipping is universal to base excision repair. Thus, this project concentrates on understanding the molecular, energetic and kinetic elements that differentiate base flipping in damaged from undamaged DNA.
Specificity of enzymes is determined not only by the recognition event, but also by the catalytic mechanism. The enzymatic catalysis of BER enzymes begins with a glycosylase step. The ionization states of several groups in the active sites of endoV or UDG are important for catalysis. We have computed the pKa values of the amino acids in the active site of endoV and on this basis we propose a catalytic mechanism of the glycosylase step in the enzyme (Fuxreiter, M. Warshel, A. Osman, R. The role of active site residues in the glycosylase step of T4 endonuclease V. Computer simulation studies on ionization states. Biochemistry, 38:9577-9589,1999). We have studied by MD simulations the reactant and product states of UDG in complex with its substrate and on the basis of structural, electrostatic and dynamic changes we propose a mechanism of catalysis for the enzyme (Luo, N. Mehler, E. Osman, R. Specificity and catalysis of uracil DNA glycosylase. A molecular dynamics study of reactant and product complexes with DNA. Biochemistry, 38:9209-9220,1999).
Miaskiewicz K, Miller J, Ornstein R, Osman R. Molecular dynamics simulations of the effects of ring-saturated thymine lesions on DNA structure. Biopolymers 1995; 35: 113-124.
Laakkonen LJ, Guarnieri F, Perlman JH, Gershengorn MC, Osman R. A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo/Stochastic Dynamics simulation of th. Biochemistry 1996; 35: 7651-7663.
Miaskiewicz K, Miller J, Cooney M, Osman R. Computatonal simulations of DNA distortions by a cis,syn-cyclobutance thymine dimer lesion. J Am Chem Soc 1996; 118: 9156-9163.
Laakkonen LJ, Li W, Perlman JH, Guarnieri F, Osman R, Moeller KD, Gershengorn MC. Restricted analogs provide evidence of a biologically active conformation of thyrotropin-releasing hormones. Mol Pharmacol 1996; 49: 1092-1096.
Perlman JH, Colson A-, Wang W, Bence K, Osman R, Gershengorn MC. Interactions between conserved residues in transmembrane helices 1,2, and 7 of the thyrotropin-releasing hormone receptor. J Biol Chem 1997; 272: 11937-11942.
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Osman did not report having any of the following types of financial relationships with industry during 2014 and/or 2015: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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