NDLI: Synthesis and characterization of an O6-2′-deoxyguanosine-alkyl-O6-2′-deoxyguanosine interstrand cross-link in a 5′-GNC motif and repair by human O6-alkylguanine-DNA alkyltransferase

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Organic & Biomolecular Chemistry Vol - 8 Issue - 9

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Synthesis and characterization of an O⁶-2′-deoxyguanosine-alkyl-O⁶-2′-deoxyguanosine interstrand cross-link in a 5′-GNC motif and repair by human O⁶-alkylguanine-DNA alkyltransferase

Content Provider	Royal Society of Chemistry (RSC)
Author	McManus, Francis P. Wilds, Christopher J. Booth, Jason D. M. Noronha, Anne M. Fang, Qingming Pegg, Anthony E.
Copyright Year	2010
Abstract	O6-2′-Deoxyguanosine-alkyl-O6-2′-deoxyguanosine interstrand DNA cross-links (ICLs) with a four and seven methylene linkage in a 5′-GNC- motif have been synthesized and their repair by human O6-alkylguanine-DNA alkyltransferase (hAGT) investigated. Duplexes containing 11 base-pairs with the ICLs in the center were assembled by automated DNA solid-phase synthesis using a cross-linked 2′-deoxyguanosine dimer phosphoramidite, prepared via a seven step synthesis which employed the Mitsunobu reaction to introduce the alkyl lesion at the O6 atom of guanine. Introduction of the four and seven carbon ICLs resulted in no change in duplex stability based on UV thermal denaturation experiments compared to a non-cross-linked control. Circular dichroism spectra of these ICL duplexes exhibited features of a B-form duplex, similar to the control, suggesting that these lesions induce little overall change in structure. The efficiency of repair by hAGT was examined and it was shown that hAGT repairs both ICL containing duplexes, with the heptyl ICL repaired more efficiently relative to the butyl cross-link. These results were reproducible with various hAGT mutants including one that contains a novel V148L mutation. The ICL duplexes displayed similar binding affinities to a C145S hAGT mutant compared to the unmodified duplex with the seven carbon containing ICLs displaying slightly higher binding. Experiments with CHO cells to investigate the sensitivity of these cells to busulfan and hepsulfam demonstrate that hAGT reduces the cytotoxicity of hepsulfam suggesting that the O6-2′-deoxyguanosine-alkyl-O6-2′-deoxyguanosine interstrand DNA cross-link may account for at least part of the cytotoxicity of this agent.
Starting Page	4414
Ending Page	4426
Page Count	13
File Format	HTM / HTML PDF
ISSN	14770520
Volume Number	8
Issue Number	19
Journal	Organic & Biomolecular Chemistry
DOI	10.1039/c0ob00093k
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Methylene bridge Crosslinking of DNA Mitsunobu reaction Butyl group Cytotoxicity Mitsunobu Solid-phase synthesis International Computers Limited Guanine Alkyl Busulfan Duplex (building) O-6-methylguanine-DNA methyltransferase Protein dimer Carbon Circular dichroism ICL Deoxyguanosine General National Congress DNA Nucleoside phosphoramidite Lesion Mutation Denaturation (biochemistry) GNC
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Physical and Theoretical Chemistry

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Engineering of a O⁶-alkylguanine-DNA alkyltransferase chimera and repair of O⁴-alkyl thymidine adducts and O⁶-alkylene-2′-deoxyguanosine cross-linked DNA

Synthesis and Characterization of Oligonucleotides Containing an O6-2′-Deoxyguanosine-Alkyl-O6-2′-Deoxyguanosine Interstrand Cross-Link in a 5′-GNC Motif and Repair by Human O6-Alkylguanine-DNA Alkyltransferase

Expression of O6-Methylguanine-DNA Methyltransferase Examined by Alkyl-Transfer Assays, Methylation-Specific PCR and Western Blots in Tumors and Matched Normal Tissue

O6-Methylguanine Repair By O6-Alkylguanine-DNA Alkyltransferase

Repair of O6-methylguanine adducts in human telomeric G-quadruplex DNA by O6-alkylguanine-DNA alkyltransferase

Synthesis and Applications of Chemical Probes for Human O6-Alkylguanine-DNA Alkyltransferase

Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase.

Quantitative relationship between guanine O6 -alkyl lesions produced by Onrigin™ and tumor resistance by O6 -alkylguanine-DNA alkyltransferase

Inactivation of O6-Alkylguanine-DNA Alkyltransferase by Folate Esters of O6-Benzyl-2‘-deoxyguanosine and of O6-[4-(Hydroxymethyl)benzyl]guanine

Synthesis and characterization of an O⁶-2′-deoxyguanosine-alkyl-O⁶-2′-deoxyguanosine interstrand cross-link in a 5′-GNC motif and repair by human O⁶-alkylguanine-DNA alkyltransferase

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