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O4-alkyl-2'-deoxythymidine cross-linked DNA to probe recognition and repair by O6-alkylguanine DNA alkyltransferases.

Author(s): McManus FP, O'Flaherty DK, Noronha AM, Wilds CJ

Org Biomol Chem. 2012 Sep 21;10(35):7078-90 Authors: McManus FP, O'Flaherty DK, Noronha AM, Wilds CJ

Article GUID: 22850722

Backbone Flexibility Influences Nucleotide Incorporation by Human Translesion DNA Polymerase η opposite Intrastrand Cross-Linked DNA.

Author(s): O'Flaherty DK, Guengerich FP, Egli M, Wilds CJ

Biochemistry. 2015 Dec 29;54(51):7449-56 Authors: O'Flaherty DK, Guengerich FP, Egli M, Wilds CJ

Article GUID: 26624500

O(6)-Alkylguanine DNA Alkyltransferase Repair Activity Towards Intrastrand Cross-Linked DNA is Influenced by the Internucleotide Linkage.

Author(s): O'Flaherty DK, Wilds CJ

Chem Asian J. 2016 Feb 18;11(4):576-83 Authors: O'Flaherty DK, Wilds CJ

Article GUID: 26692563

Lesion Orientation of O4-Alkylthymidine Influences Replication by Human DNA Polymerase η.

Author(s): O'Flaherty DK, Patra A, Su Y, Guengerich FP, Egli M, Wilds CJ

Chem Sci. 2016 Aug 01;7(8):4896-4904 Authors: O'Flaherty DK, Patra A, Su Y, Guengerich FP, Egli M, Wilds CJ

Article GUID: 27574558

Preparation of Intrastrand {G}O(6) -Alkylene-O(6) {G} Cross-Linked Oligonucleotides.

Author(s): O'Flaherty DK, Wilds CJ

Curr Protoc Nucleic Acid Chem. 2016 09 01;66:5.17.1-5.17.24 Authors: O'Flaherty DK, Wilds CJ

Article GUID: 27584704

O6-2'-Deoxyguanosine-butylene-O6-2'-deoxyguanosine DNA Interstrand Cross-Links Are Replication-Blocking and Mutagenic DNA Lesions.

Author(s): Xu W, Kool D, O'Flaherty DK, Keating AM, Sacre L, Egli M, Noronha A, Wilds CJ, Zhao L

Chem Res Toxicol. 2016 11 21;29(11):1872-1882 Authors: Xu W, Kool D, O'Flaherty DK, Keating AM, Sacre L, Egli M, Noronha A, Wilds CJ, Zhao L

Article GUID: 27768841

Site-specific covalent capture of human O6-alkylguanine-DNA-alkyltransferase using single-stranded intrastrand cross-linked DNA.

Author(s): O'Flaherty DK, Wilds CJ

Org Biomol Chem. 2016 Dec 20;15(1):189-196 Authors: O'Flaherty DK, Wilds CJ

Article GUID: 27886318

Structural basis of interstrand cross-link repair by O6-alkylguanine DNA alkyltransferase.

Author(s): Denisov AY, McManus FP, O'Flaherty DK, Noronha AM, Wilds CJ

Org Biomol Chem. 2017 Oct 11;15(39):8361-8370 Authors: Denisov AY, McManus FP, O'Flaherty DK, Noronha AM, Wilds CJ

Article GUID: 28937154

AGT Activity Towards Intrastrand Crosslinked DNA is Modulated by the Alkylene Linker.

Author(s): O'Flaherty DK, Wilds CJ

Chembiochem. 2017 12 05;18(23):2351-2357 Authors: O'Flaherty DK, Wilds CJ

Article GUID: 28980757

Altering Residue 134 Confers an Increased Substrate Range of Alkylated Nucleosides to the E. coli OGT Protein.

Author(s): Schoonhoven NM, O'Flaherty DK, McManus FP, Sacre L, Noronha AM, Kornblatt MJ, Wilds CJ

Molecules. 2017 Nov 11;22(11): Authors: Schoonhoven NM, O'Flaherty DK, McManus FP, Sacre L, Noronha AM, Kornblatt MJ, Wilds CJ

Article GUID: 29137116

Covalent capture of OGT's active site using engineered human-E. coli chimera and intrastrand DNA cross-links.

Author(s): Copp W, O'Flaherty DK, Wilds CJ

Org Biomol Chem. 2018 11 28;16(46):9053-9058 Authors: Copp W, O'Flaherty DK, Wilds CJ

Article GUID: 30430154


Title:O4-alkyl-2'-deoxythymidine cross-linked DNA to probe recognition and repair by O6-alkylguanine DNA alkyltransferases.
Authors:McManus FPO'Flaherty DKNoronha AMWilds CJ
Link:https://www.ncbi.nlm.nih.gov/pubmed/22850722?dopt=Abstract
DOI:10.1039/c2ob25705j
Category:Org Biomol Chem
PMID:22850722
Dept Affiliation: CHEMBIOCHEM
1 Department of Chemistry and Biochemistry, Concordia University, Montreal, Canada.

Description:

O4-alkyl-2'-deoxythymidine cross-linked DNA to probe recognition and repair by O6-alkylguanine DNA alkyltransferases.

Org Biomol Chem. 2012 Sep 21;10(35):7078-90

Authors: McManus FP, O'Flaherty DK, Noronha AM, Wilds CJ

Abstract

DNA duplexes containing a directly opposed O(4)-2'-deoxythymidine-alkyl-O(4)-2'-deoxythymidine (O(4)-dT-alkyl-O(4)-dT) interstrand cross-link (ICL) have been prepared by the synthesis of cross-linked nucleoside dimers which were converted to phosphoramidites to produce site specific ICL. ICL duplexes containing alkyl chains of four and seven methylene groups were prepared and characterized by mass spectrometry and nuclease digests. Thermal denaturation experiments revealed four and seven methylene containing ICL increased the T(m) of the duplex with respect to the non-cross-linked control with an observed decrease in enthalpy based on thermodynamic analysis of the denaturation curves. Circular dichroism experiments on the ICL duplexes indicated minimal difference from B-form DNA structure. These ICL were used for DNA repair studies with O(6)-alkylguanine DNA alkyltransferase (AGT) proteins from human (hAGT) and E. coli (Ada-C and OGT), whose purpose is to remove O(6)-alkylguanine and in some cases O(4)-alkylthymine lesions. It has been previously shown that hAGT can repair O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine ICL. The O(4)-dT-alkyl-O(4)-dT ICL prepared in this study were found to evade repair by hAGT, OGT and Ada-C. Electromobility shift assay (EMSA) results indicated that the absence of any repair by hAGT was not a result of binding. OGT was the only AGT to show activity in the repair of oligonucleotides containing the mono-adducts O(4)-butyl-4-ol-2'-deoxythymidine and O(4)-heptyl-7-ol-2'-deoxythymidine. Binding experiments conducted with hAGT demonstrated that the protein bound O(4)-alkylthymine lesions with similar affinities to O(6)-methylguanine, which hAGT repairs efficiently, suggesting the lack of O(4)-alkylthymine repair by hAGT is not a function of recognition.

PMID: 22850722 [PubMed - indexed for MEDLINE]