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Albany 2015:Book of Abstracts

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

Role of Dynamic Base Pair Polymorphism in the Central Dogma of Molecular Biology

NMR spin relaxation in the rotating frame (R1rho) experiments are described for characterizing transient excursions in nucleic acid duplexes that are directed toward short-lived (lifetimes of milliseconds to seconds) and low populated (10%-0.001%) excited states. The NMR chemical shifts are used to infer the structure of the excited states, and chemical modifications are used to trap, stabilize or destabilize a suspected excited state structure. Computational approaches, including density functional theory calculations, are also used to predict chemical shifts of the proposed excited state structure and to evaluate whether the transitions are stereochemically feasible. With this approach, we have uncovered two basic modes of base pair dynamics in nucleic acid duplexes. In one mode, canonical A-T and G-C Watson-Crick base pairs transition toward non-canonical Hoogsteen base pairs in which the purine base adopts a syn rather than anti conformation. Such transitions occur in B-form DNA but are highly unfavorable in A-form RNA. In a second mode, non-canonical G-T mispairs transition toward canonical Watson-Crick like base pairs through ionization and tautomerization of the bases. These transitions occur equally in B-form DNA and A-form RNA duplexes. The roles of these two dynamic modes in maintenance of genomic stability, sequence-specific recognition, damage induction and repair, and spontaneous mutations will be discussed.

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This work was supported by an NIH grant (R01GM089846) and an Agilent Thought Leader Award given to H.M.A.

References
    Kimsey I, Petzold K, Sathyamoorthy B, Stein Z, and Al-Hashimi HM Visualizing Transient Watson-Crick Like Mispairs in DNA and RNA Duplexes Nature, In Press

    Alvey HS, Gottardo FL, Nikolova EN, Al-Hashimi HM, Widespread Transient Hoogsteen Base-Pairs in Canonical Duplex DNA with Variable Energetics Nat Communications 5:4786 2014

    Nikolova E Kim E Wise A O'Brien P Andricioaei I and Al-Hashimi HM Transient Hoogsteen Base-pairs in Canonical Duplex DNA Nature 470(7335):498-502 2011


Isaac J. Kimsey
Huiqing Zhou
Heidi Alvey
Hashim M. Al-Hashimi

Department of Biochemistry and Chemistry
Duke University Medical Center
Durham, NC 27710, USA

Ph: 919-684-4325
Fx: 919-684-8885
hashim.al.hashimi@duke.edu