Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Repair of o(6)-g-alkyl-o(6)-g interstrand cross-links by human o(6)-alkylguanine-DNA alkyltransferase

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Fang, Q. M.
  • Noronha, A. M.
  • Murphy, S. P.
  • Wilds, C. J.
  • Tubbs, Julie
  • Tainer, John
  • Chowdhury, G.
  • Guengerich, F. P.
  • Pegg, A. E.

publication date

  • October 2008

journal

  • Biochemistry  Journal

abstract

  • O (6)-Alkylguanine-DNA alkyltransferase (AGT) plays an important role by protecting cells from alkylating agents. This reduces the frequency of carcinogenesis and mutagenesis initiated by such agents, but AGT also provides a major resistance mechanism to some chemotherapeutic drugs. To improve our understanding of the AGT-mediated repair reaction and our understanding of the spectrum of repairable damage, we have studied the ability of AGT to repair interstrand cross-link DNA damage where the two DNA strands are joined via the guanine- O (6) in each strand. An oligodeoxyribonucleotide containing a heptane cross-link was repaired with initial formation of an AGT-oligo complex and further reaction of a second AGT molecule yielding a hAGT dimer and free oligo. However, an oligodeoxyribonucleotide with a butane cross-link was a very poor substrate for AGT-mediated repair, and only the first reaction that forms an AGT-oligo complex could be detected. Models of the reaction of these substrates in the AGT active site show that the DNA duplex is forced apart locally to repair the first guanine. This reaction is greatly hindered with the butane cross-link, which is mostly buried in the active site pocket and limited in conformational flexibility. This limitation also prevents the adoption of a conformation for the second reaction to repair the AGT-oligo complex. These results are consistent with the postulated mechanism of AGT repair that involves DNA binding and flipping of the substrate nucleotide and indicate that hAGT can repair some types of interstrand cross-link damage.

subject areas

  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • DNA Damage
  • DNA Modification Methylases
  • DNA Repair
  • DNA Repair Enzymes
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Models, Molecular
  • Tumor Suppressor Proteins
scroll to property group menus

Identity

PubMed Central ID

  • PMC2632579

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi8008664

PubMed ID

  • 18803403
scroll to property group menus

Additional Document Info

start page

  • 10892

end page

  • 10903

volume

  • 47

issue

  • 41

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support