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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
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
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:Structural basis of interstrand cross-link repair by O6-alkylguanine DNA alkyltransferase.
Authors:Denisov AY,  McManus FP,  O'Flaherty DK,  Noronha AM,  Wilds CJ
Link:https://www.ncbi.nlm.nih.gov/pubmed/28937154?dopt=Abstract
Category:Org Biomol Chem
PMID:28937154
Dept Affiliation: CHEMBIOCHEM
1 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, Québec, Canada. chris.wilds@concordia.ca.

Description:

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

Org Biomol Chem. 2017 Oct 11;15(39):8361-8370

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

Abstract

DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems. O6-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the O6-atom of 2'-deoxyguanosine and the O4-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two O6-atoms of 2'-deoxyguanosine were tethered by a butylene (XLGG4) or heptylene (XLGG7) linkage. However, the analogous ICL between the O4-atoms of thymidine was found to evade repair. ICL duplexes connecting the O4-atoms of 2'-deoxyuridine by a butylene (XLUU4) or heptylene (XLUU7) linkage have been prepared to examine the influence of the C5-methyl group on AGT-mediated repair. Both XLUU4 and XLUU7 were refractory to repair by human and E. coli (OGT and Ada-C) AGTs with comparably low µM dissociation constants for 2?:?1 or 4?:?1 AGT/DNA stoichiometries. The solution structures of two heptylene linked DNA duplexes (CGAAAYTTTCG)2, XLUU7 (Y = dU) and XLGG7 (Y = dG), were solved and the global structures were virtually identical with a RMSD of 1.22 Å. The ICL was found to reside in the major groove for both duplexes. The linkage adopts an E conformation about the C4-O4 bond for XLUU7 whereas a Z conformation about the C6-O6 bond was observed for XLGG7. This E versus Z conformation may partially account for hAGTs discrimination towards the repair of these ICL, supported by the crystal structures of hAGT with various substrates which have been observed to adopt a Z conformation. In addition, a higher mobility at the ICL site for XLUU7 is observed relative to XLGG7 that may play a role in repair by hAGT. Taken together, these findings provide insights on the AGT-mediated repair of cytotoxic ICL in terms of its processing capability and substrate specificity.

PMID: 28937154 [PubMed - indexed for MEDLINE]