New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey

Zhou, Huiqing; Hintze, Bradley J.; Kimsey, Isaac J.; Sathyamoorthy, Bharathwaj; Shan, Yang; Richardson, Jane S.; Al‐Hashimi, Hashim M.

doi:10.1093/nar/gkv241

Cited by 71 publications

(125 citation statements)

References 80 publications

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“…In addition, the perturbations induced by m 1 A•T HG bps observed in our study are also observed in X-ray structures of unmodified DNA duplexes containing HG bps bound to proteins (40). Nevertheless, we cannot entirely rule out that the methyl group in m 1 A•T could affect HG pairing as compared to unmodified HG bps due to presence of the methyl group and/or the positive charge on the adenine base which can also affect electronic properties and stacking interactions (21).…”

Section: Discussionsupporting

confidence: 75%

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Sathyamoorthy

Shi

Zhou

et al. 2017

Nucleic Acids Research

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123

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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.

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Section: Discussionsupporting

confidence: 75%

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Sathyamoorthy

Shi

Zhou

et al. 2017

Nucleic Acids Research

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123

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“…This change in sugar pucker in turn leads to major groove kinking of the duplex at the Hoogsteen bp (Figure 7C and 7D). This helps to rationalize the observed correlation between pyrimidine-purine distance and the magnitude of major groove kinking 72 .…”

Section: Resultsmentioning

confidence: 74%

Atomic structures of excited state A–T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations

et al. 2018

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NMR relaxation dispersion studies indicate that in canonical duplex DNA, Watson-Crick base pairs (bps) exist in dynamic equilibrium with short-lived low abundance excited state Hoogsteen bps. N1-methylated adenine (m1A) and guanine (m1G) are naturally occurring forms of damage that stabilize Hoogsteen bps in duplex DNA. NMR dynamic ensembles of DNA duplexes with m1A-T Hoogsteen bps reveal significant changes in sugar pucker and backbone angles in and around the Hoogsteen bp, as well as kinking of the duplex towards the major groove. Whether these structural changes also occur upon forming excited state Hoogsteen bps in unmodified duplexes remains to be established because prior relaxation dispersion probes provided limited information regarding the sugar-backbone conformation. Here, we demonstrate measurements of C3′ and C4′ spin relaxation in the rotating frame (R1ρ) in uniformly 13C/15N labeled DNA as sensitive probes of the sugar-backbone conformation in DNA excited states. The chemical shifts, combined with structure-based predictions using an Automated Fragmentation Quantum Mechanics/Molecular Mechanics (AFQM/MM) method, show that the dynamic ensemble of DNA duplexes containing m1A-T Hoogsteen bps accurately model the excited state Hoogsteen conformation in two different sequence contexts. Formation of excited state A-T Hoogsteen bps is accompanied by changes in sugar-backbone conformation that allow the flipped syn adenine to form hydrogen-bonds with its partner thymine and this in turn results in overall kinking of the DNA toward the major groove. Results support the assignment of Hoogsteen bps as the excited state observed in canonical duplex DNA, provide an atomic view of DNA dynamics linked to formation of Hoogsteen bps, and lay the groundwork for a potentially general strategy for solving structures of nucleic acid excited states.

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“…This is consistent with a recent study. 102 which found similar alterations to these angles in a structure-based survey of the PDB.…”

Section: Discussionmentioning

confidence: 65%

Robust IR‐based detection of stable and fractionally populated G‐C⁺ and A‐T Hoogsteen base pairs in duplex DNA

Stelling

Zhou

et al. 2017

FEBS Letters

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Non-canonical G-C+ and A-T Hoogsteen base pairs can form in duplex DNA and play roles in recognition, damage repair, and replication. Identifying Hoogsteen base pairs in DNA duplexes remains challenging due to difficulties in resolving syn versus anti purine bases with X-ray crystallography; and size limitations and line broadening can make them difficult to characterize by NMR spectroscopy. Here, we show how infrared (IR) spectroscopy can identify G-C+ and A-T Hoogsteen base pairs in duplex DNA across a range of different structural contexts. The utility of IR-based detection of Hoogsteen base pairs is demonstrated by characterizing the first example of adjacent A-T and G-C+ Hoogsteen base pairs in a DNA duplex where severe broadening complicates detection with NMR.

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New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey

Cited by 71 publications

References 80 publications

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Atomic structures of excited state A–T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations

Robust IR‐based detection of stable and fractionally populated G‐C⁺ and A‐T Hoogsteen base pairs in duplex DNA

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New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey

Cited by 71 publications

References 80 publications

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A

Atomic structures of excited state A–T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations

Robust IR‐based detection of stable and fractionally populated G‐C+ and A‐T Hoogsteen base pairs in duplex DNA

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Product

Resources

About

Robust IR‐based detection of stable and fractionally populated G‐C⁺ and A‐T Hoogsteen base pairs in duplex DNA