Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

How is fidelity maintained in nucleic acids? Two tales in DNA repair and DNA transcription from computer simulations

Fidelity during nucleic acid replication and transcription is essential for maintaining proper biological function and involves a variety of different mechanisms. After replication, DNA repair processes correct base mismatches and insertion or deletions. A key step in this process is the recognition of DNA lesions by the post-replication mismatch recognition protein MutS and homologs. Results from extensive fully atomistic computer simulations reveal how MutS recognizes mismatches via bending DNA, how specificity towards mismatches vs. insertions is achieved in divergent eukaryotic MutS homologs, and how MutS signals the need for repair by other enzymes once a mismatch is found.

Fidelity is also examined in the context of RNA polymerase where faithful transcription from a DNA template to RNA requires that correctly templated ribonucleotides are reliably discriminated from mismatches and deoxyribonucleotides when polymerase elongates the nascent RNA. Results from biased and unbiased explicit solvent fully atomistic computer simulations suggest a number of steps by which fidelity is achieved and provide details about the mechanistic steps that are involved in the successful addition of a correct nucleotide.

This research has been supported by NSF MCB 0447799 and NIH R01 GM092949

    B. Wang, K. Opron, Z. F. Burton, R. I. Cukier, M. Feig: Five checkpoints maintaining the fidelity of transcription by RNA polymerases in structural and energetic detail. Nucleic Acids Research (2015), in press

    B. Wang, A. Predeus, Z. Burton, M. Feig: Energetic and Structural Details of Trigger Loop Closing Transition in RNA Polymerase II. Biophysical Journal (2013), 105, 767-775

    M. Sharma, A Predeus, S. Mukherjee, M. Feig: DNA Bending Propensity in the Presence of Base Mismatches: Implications for DNA Repair. Journal of Physical Chemistry B (2013), 117, 6194-6205

    S. M. Law, M. Feig: Base-flipping mechanism in DNA mismatch recognition by MutS. Biophysical Journal (2011), 101, 2223-2231

    M. Feig, Z. Burton: RNA Polymerase II with Open and Closed Trigger Loops: Active Site Dynamics and Nucleic Acid Translocation. Biophysical Journal (2010) 99, 2577-2586

    S. Mukherjee, M. Feig: Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity. Biophysical Journal (2009), 96, L63-L65

Michael Feig
Beibei Wang
Monika Sharma
Zachary Burton
Kristopher Opron
Robert Cukier
Alexander Predeus
Nicholas Kovacs
Sean Law
Shayantani Mukherjee

Department of Biochemistry and Molecular Biology and Department of Chemistry
Michigan State University
East Lansing, MI 48824

Ph: (517) 432-7439