Nucleic Acids Research, Vol 26, Issue 4 932-941, Copyright © 1998 by Oxford University Press
L Harrison, Z Hatahet, AA Purmal and SS Wallace
Bursts of free radicals produced by ionization of water in close vicinity
to DNA can produce clusters of opposed DNA lesions and these are termed
multiply damaged sites (MDS). How MDS are processed by the Escherichia coli
DNA glycosylases, endonuclease (endo) III and endo VIII, which recognize
oxidized pyrimidines, is the subject of this study. Oligonucleotide
substrates were constructed containing a site of pyrimidine damage or an
abasic (AP) site in close proximity to a single nucleotide gap, which
simulates a free radical-induced single-strand break. The gap was placed in
the opposite strand 1, 3 or 6 nt 5' or 3' of the AP site or base lesion.
Endos III and VIII were able to cleave an AP site in the MDS, no matter
what the position of the opposed strand break, although cleavage at
position one 5' or 3' was reduced compared with cleavage at positions three
or six 5' or 3'. Neither endo III nor endo VIII was able to remove the base
lesion when the gap was positioned 1 nt 5' or 3' in the opposite strand.
Cleavage of the modified pyrimidine by endo III increased as the distance
increased between the base lesion and the opposed strand break. With endo
VIII, however, DNA breakage at the site of the base lesion was equivalent
to or less when the gap was positioned 6 nt 3' of the lesion than when the
gap was 3 nt 3' of the lesion. Gel mobility shift analysis of the binding
of endo VIII to an oligonucleotide containing a reduced AP (rAP) site in
close opposition to a single nucleotide gap correlated with cleavage of MDS
substrates by endo VIII. If the strand break in the MDS was replaced by an
oxidized purine, 7,8-dihydro-8-oxoguanine (8- oxoG), neither endo VIII
cleavage nor binding were perturbed. These data show that processing of
oxidized pyrimidines by endos III and VIII was strongly influenced by the
position and type of lesion in the opposite strand, which could have a
significant effect on the biological outcome of the MDS lesion.
ARTICLES
Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII
Department of Microbiology and Molecular Genetics, Markey Center for Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
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