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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
Preparation of covalently linked complexes between DNA and O(6)-alkylguanine-DNA alkyltransferase using interstrand cross-linked DNA.

Author(s): McManus FP, Khaira A, Noronha AM, Wilds CJ

Bioconjug Chem. 2013 Feb 20;24(2):224-33 Authors: McManus FP, Khaira A, Noronha AM, Wilds CJ

Article GUID: 23347328
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
Influence of nucleotide modifications at the C2' position on the Hoogsteen base-paired parallel-stranded duplex of poly(A) RNA.

Author(s): Copp W, Denisov AY, Xie J, Noronha AM, Liczner C, Safaee N, Wilds CJ, Gehring K

Nucleic Acids Res. 2017 Sep 29;45(17):10321-10331 Authors: Copp W, Denisov AY, Xie J, Noronha AM, Liczner C, Safaee N, Wilds CJ, Gehring K

Article GUID: 28973475
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
Title:Altering Residue 134 Confers an Increased Substrate Range of Alkylated Nucleosides to the E. coli OGT Protein.
Authors:Schoonhoven NM,  O'Flaherty DK,  McManus FP,  Sacre L,  Noronha AM,  Kornblatt MJ,  Wilds CJ
Link:https://www.ncbi.nlm.nih.gov/pubmed/29137116?dopt=Abstract
Category:Molecules
PMID:29137116
Dept Affiliation: CHEMBIOCHEM
1 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. nadiaschoonhoven@hotmail.com.
2 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. derek_oflaherty@hotmail.com.
3 Howard Hughes Medical Institute, Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. derek_oflaherty@hotmail.com.
4 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. shent13@hotmail.com.
5 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada. shent13@hotmail.com.
6 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. dlsacre@hotmail.com.
7 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. anne.noronha@concordia.ca.
8 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. Judith.Kornblatt@concordia.ca.
9 Department of Chemistry and Biochemistry, Concordia University, Montréal, QC H4B 1R6, Canada. Chris.Wilds@concordia.ca.

Description:

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

Molecules. 2017 Nov 11;22(11):

Authors: Schoonhoven NM, O'Flaherty DK, McManus FP, Sacre L, Noronha AM, Kornblatt MJ, Wilds CJ

Abstract

O6-Alkylguanine-DNA alkyltransferases (AGTs) are proteins responsible for the removal of mutagenic alkyl adducts at the O6-atom of guanine and O4-atom of thymine. In the current study we set out to understand the role of the Ser134 residue in the Escherichia coli AGT variant OGT on substrate discrimination. The S134P mutation in OGT increased the ability of the protein to repair both O6-adducts of guanine and O4-adducts of thymine. However, the S134P variant was unable, like wild-type OGT, to repair an interstrand cross-link (ICL) bridging two O6-atoms of guanine in a DNA duplex. When compared to the human AGT protein (hAGT), the S134P OGT variant displayed reduced activity towards O6-alkylation but a much broader substrate range for O4-alkylation damage reversal. The role of residue 134 in OGT is similar to its function in the human homolog, where Pro140 is crucial in conferring on hAGT the capability to repair large adducts at the O6-position of guanine. Finally, a method to generate a covalent conjugate between hAGT and a model nucleoside using a single-stranded oligonucleotide substrate is demonstrated.

PMID: 29137116 [PubMed - indexed for MEDLINE]