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Recognition of Abasic Sites and Single Base Bulges in DNA by a Metalloinsertor†
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Financial support for this work from the National Institutes of Health (GM33309 to J.K.B.) is gratefully acknowledged.
, * To whom correspondence should be addressed. E-mail: jkbarton@caltech.edu. Tel: (626) 395-6075. Fax: (626) 577-4976.
Section:Abstract
Abasic sites and single base bulges are thermodynamically destabilizing DNA defects that can lead to cancerous transformations if left unrepaired by the cell. Here we discuss the binding properties with abasic sites and single base bulges of Rh(bpy)2(chrysi)3+, a complex previously shown to bind thermodynamically destabilized mismatch sites via metalloinsertion. Photocleavage experiments show that Rh(bpy)2(chrysi)3+ selectively binds abasic sites with affinities of 1−4 × 106 M−1; specific binding is independent of unpaired base identity but is somewhat contingent on sequence context. Single base bulges are also selectively bound and cleaved, but in this case, the association constants are significantly lower (
105 M−1), and the binding is dependent on both unpaired base identity and bulge sequence context. A wide variety of evidence, including strand scission asymmetry, binding enantiospecificity, and MALDI-TOF cleavage fragment analysis, suggests that Rh(bpy)2(chrysi)3+ binds abasic sites, like mismatches, through insertion of the bulky chrysi ligand into the base pair stack from the minor groove side and ejection of the unpaired base. At single base bulge sites, a similar, though not identical, metalloinsertion mode is suggested. The recognition of abasic sites and single base bulges with bulky metalloinsertors holds promise for diagnostic and therapeutic applications.
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This article has been cited by 5 ACS Journal articles (5 most recent appear below).
Detecting DNA Mismatches with Metallo-Insertors: A Molecular Simulation Study
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Attilio V. Vargiu and Alessandra MagistratoInorganic Chemistry2012 Article ASAPMolecules that selectively recognize DNA mismatches (MMs) play a key role as nucleic acids probes and as chemotherapeutic agents. Metallo-insertors bind to the minor groove (mG) of double strand (ds) DNA, expelling the mismatched base pairs and acting as ...
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Sensitivity of Ru(bpy)2dppz2+ Luminescence to DNA Defects
Mi Hee Lim, Hang Song, Eric D. Olmon, Elizabeth E. Dervan and Jacqueline K. BartonInorganic Chemistry2009 48 (12), 5392-5397Sensitivity of Ru(bpy)2dppz2+ Luminescence to DNA Defects
Mi Hee Lim, Hang Song, Eric D. Olmon, Elizabeth E. Dervan and Jacqueline K. BartonInorganic Chemistry2009 48 (12), 5392-5397Ru(bpy)2dppz2+, a DNA light switch for well matched duplex DNA, shows higher luminescence with DNA mismatches and DNA containing abasic sites. Studies support metalloinsertion as the binding mode for the Ru complex at the defect site.
A Bulky Rhodium Complex Bound to an Adenosine-Adenosine DNA Mismatch: General Architecture of the Metalloinsertion Binding Mode
Brian M. Zeglis, Valérie C. Pierre, Jens T. Kaiser and Jacqueline K. BartonBiochemistry2009 48 (20), 4247-4253A Bulky Rhodium Complex Bound to an Adenosine-Adenosine DNA Mismatch: General Architecture of the Metalloinsertion Binding Mode
Brian M. Zeglis, Valérie C. Pierre, Jens T. Kaiser and Jacqueline K. BartonBiochemistry2009 48 (20), 4247-4253Two crystal structures of Δ-Rh(bpy)2(chrysi)3+ (chrysi is 5,6-chrysenequinone diimine) bound to the oligonucleotide duplex 5′-CGGAAATTACCG-3′ containing two adenosine-adenosine mismatches (italics) through metalloinsertion were determined. Diffraction ...
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History
- Published In Issue February 10, 2009
- Article ASAPJanuary 15, 2009
- Received: October 6, 2008
Revised: December 2, 2008
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