Direct Measurement of 8OGsyn-antiFlips in Mutagenic 8OG•A and Long-Range Damage-Dependent Hoogsteen Breathing Dynamics Using1H CEST NMR

Author:

Gu Stephanie,Al-Hashimi Hashim M.

Abstract

ABSTRACTElucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter the propensities to form lowly-populated and short-lived conformational states. However, NMR methods to measure these dynamics require isotopic enrichment, which is difficult for damaged nucleotides. Here, we demonstrate the utility of the1H chemical exchange saturation transfer (CEST) NMR experiment in measuring the dynamics of oxidatively damaged 8-oxoguanine (8OG) in the mutagenic 8OGsyn•Aantimismatch. Using 8OG-H7 as an NMR probe of the damaged base, we directly measured 8OGsyn-antiflips to form a lowly-populated (pop. ∼ 5%) and short-lived (lifetime ∼ 50 ms) non-mutagenic 8OGanti•Aanti. These exchange parameters were in quantitative agreement with values from13C off-resonanceRand CEST on a labeled partner adenine. The Watson-Crick-like 8OGsyn•Aantimismatch also rescued the kinetics of Hoogsteen motions at distance A-T base pairs, which the G•A mismatch had slowed down. The results lend further support for 8OGanti•Aantias a minor conformational state of 8OG•A, reveal that 8OG damage can impact Hoogsteen dynamics at a distance, and demonstrate the utility of1H CEST for measuring damage-dependent dynamics in unlabeled DNA.

Publisher

Cold Spring Harbor Laboratory

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