title: Insights into Watson-Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A.
abstract: In the canonical DNA double helix, Watson-Crick (WC) base pairs (bps) exist in dynamic equilibrium with sparsely populated (∼0.02-0.4%) and short-lived (lifetimes ∼0.2-2.5 ms) Hoogsteen (HG) bps. To gain insights into transient HG bps, we used solution-state nuclear magnetic resonance spectroscopy, including measurements of residual dipolar couplings and molecular dynamics simulations, to examine how a single HG bp trapped using the N1-methylated adenine (m1A) lesion affects the structural and dynamic properties of two duplexes. The solution structure and dynamic ensembles of the duplexes reveals that in both cases, m1A forms a m1A•T HG bp, which is accompanied by local and global structural and dynamic perturbations in the double helix. These include a bias toward the BI backbone conformation; sugar repuckering, major-groove directed kinking (∼9°); and local melting of neighboring WC bps. These results provide atomic insights into WC/HG breathing dynamics in unmodified DNA duplexes as well as identify structural and dynamic signatures that could play roles in m1A recognition and repair.
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.|Department of Chemistry, Duke University, Durham, NC 27710, USA.
authors.forename: Bharathwaj
authors.initials: B
authors.lastname: Sathyamoorthy
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27710, USA.
authors.forename: Honglue
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.|Department of Chemistry, Duke University, Durham, NC 27710, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Rangadurai
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27710, USA.
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Merriman
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.|Department of Chemistry, Duke University, Durham, NC 27710, USA.
authors.forename: Hashim M
authors.initials: HM
authors.lastname: Al-Hashimi
mesh_terms: D000225:Adenine / Q000737:chemistry*; D020029:Base Pairing; D004247:DNA / Q000737:chemistry*; D004260:DNA Repair; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D009690:Nucleic Acid Conformation; D012996:Solutions; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D012996:Solutions; D004247:DNA; D000225:Adenine