2008
DOI: 10.1093/nar/gkn512
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Interactions between branched DNAs and peptide inhibitors of DNA repair

Abstract: The RecG helicase of Escherichia coli unwinds both Holliday junction (HJ) and replication fork DNA substrates. Our lab previously identified and characterized peptides (WRWYCR and KWWCRW) that block the activity of RecG on these substrates. We determined that the peptides bind HJ DNA and prevent the binding of RecG. Herein, we present further evidence that the peptides are competitive inhibitors of RecG binding to its substrates. We have generated structural models of interactions between WRWYCR and a junction… Show more

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Cited by 30 publications
(44 citation statements)
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“…The peptide binds to branched DNA molecules, with the peptide having the highest affinities for Holliday junctions and somewhat lower levels of affinity for complete or partial replication forks (those that have only the leading or the lagging strand) (25,26). Such structures are expected to arise when replication forks regress or when they collapse when they encounter double-strand breaks or nicks; covalent protein-DNA intermediates, such as those that occur during abortive topoisomerase reactions; and interstrand cross-links, among others (14,15,28).…”
Section: Discussionmentioning
confidence: 99%
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“…The peptide binds to branched DNA molecules, with the peptide having the highest affinities for Holliday junctions and somewhat lower levels of affinity for complete or partial replication forks (those that have only the leading or the lagging strand) (25,26). Such structures are expected to arise when replication forks regress or when they collapse when they encounter double-strand breaks or nicks; covalent protein-DNA intermediates, such as those that occur during abortive topoisomerase reactions; and interstrand cross-links, among others (14,15,28).…”
Section: Discussionmentioning
confidence: 99%
“…As they are dimers via a disulfide bridge, they recognize and bind to four-arm (Holliday) junctions (K d , 12 to 14 nM) and bind with a reduced affinity and lesser stability to three-arm DNA structures that mimic replication forks (K d , 64 to 132 nM) (25,26; J. Boldt, R. Saha, J. Arciniega, and A. M. Segall, unpublished results). This enables the peptides to inhibit a number of structurally and mechanistically unrelated proteins that process HJs, D loops, and related DNA intermediates of DNA repair (10,22,25,26).Both WRWYCR and wrwycr inhibit bacterial growth in a dose-dependent manner, with wrwycr showing greater potency at longer incubation times, presumably due to its resistance to proteases. MIC assays showed that Gram-negative bacteria (Escherichia coli, Salmonella) were less sensitive to the peptide (64 M) than Gram-positive bacteria (Bacillus subtilis, Lactococcus lactis, Listeria monocytogenes, Staphylococcus aureus, methicillin-resistant S. aureus) and Gram-negative bacteria with mutationally shortened lipopolysaccharide (LPS) chains (8 to 32 M), while viability assays revealed that the peptides are bactericidal at 1ϫ to 2ϫ MICs (22).…”
mentioning
confidence: 96%
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“…The peptides have been characterized extensively and inhibit recombination by binding to the HJ intermediate and by preventing further catalysis (4,20,21), probably by altering the three-dimensional structure of the junction, moving the path of the phosphodiester backbone away from Int's active site (16). Because it binds HJ and, with lesser affinity and stability, other branched DNA intermediates (21), the peptide wrwycr inhibits a number of HJ processing enzymes in a structure-selective manner (20,21). This peptide has also been shown to have antimicrobial activity (18) and inhibits Salmonella growing inside macrophages (L. Su, D. Hall, and A. Segall, unpublished data).…”
Section: Discussionmentioning
confidence: 99%
“…Among the best characterized of these is the Damino acid hexapeptide wrwycr. This peptide binds HJs and other branched DNA intermediates, the latter with lesser affinity and stability, and by doing so, is able to inhibit a number of HJ processing enzymes in a structureselective manner (Kepple et al, 2005(Kepple et al, , 2008. During sitespecific recombination mediated by bacteriophage lambda integrase, an HJ intermediate is generated after the first round of DNA cleavage, strand exchange and ligation, and is resolved in a second round of the same catalytic steps (Azaro & Landy, 2002).…”
Section: Introductionmentioning
confidence: 99%