Document Detail


DNA sequence context conceals α-anomeric lesions.
MedLine Citation:
PMID:  22227386     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an α-anomeric adenosine (αA) flanked by cytosines (5'CαAC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'CαAG-3' motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5'CαAG-3' core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total R(X) <5.3%). The αA base is intrahelical, in a reverse Watson-Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5'CαAC-3' core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5'CαAC-3' sequence. The improved stacking of the 5'CαAG-3' core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV.
Authors:
Christopher N Johnson; Alexander M Spring; Sunil Desai; Richard P Cunningham; Markus W Germann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-29
Journal Detail:
Title:  Journal of molecular biology     Volume:  416     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-03-30     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  425-37     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Computer Simulation
DNA / chemistry*
DNA Damage*
Deoxyribonuclease IV (Phage T4-Induced) / chemistry
Models, Molecular*
Nucleic Acid Conformation*
Thermodynamics
Grant Support
ID/Acronym/Agency:
C06RR0154464/RR/NCRR NIH HHS; GM46312/GM/NIGMS NIH HHS; R01 AI047459-06/AI/NIAID NIH HHS; R01 CA076011-05/CA/NCI NIH HHS; R01 GM046312/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
9007-49-2/DNA; EC 3.1.21.2/Deoxyribonuclease IV (Phage T4-Induced)
Comments/Corrections

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