Abstract:
:Abasic lesions are common mutagenic or cytotoxic DNA damages. Ape1 is the major human apurinic/apyrimidinic (AP) endonuclease and initiates repair of abasic sites by catalyzing strand cleavage at the lesion. I show here that Ape1 single-stranded (ss) AP site incision activity prefers 0.5 mM or 2 mM MgCl(2) and low concentrations (< or =50 mM) of KCl, whereas its double-stranded (ds) activity favors 10 mM MgCl(2) and 50 mM KCl or 2 mM MgCl(2) and 200 mM KCl. Both activities favor a pH between 7.0 and 7.5, suggesting a common catalytic mechanism. In conditions designed to mimic the intracellular environment (pH 7.2; 100 mM KCl; 1 mM MgCl(2)), Ape1 ssAP site incision activity is either about fivefold more active or approximately 20-fold less efficient than its ds activity, depending on the oligonucleotide employed. Secondary structure predictions suggest a role for the DNA conformational state in determining the effectiveness of Ape1. Ape1 complex stability in the presence of EDTA (non-incising conditions) is significantly weaker for ssDNA than dsDNA, regardless of the AP substrate. Duplexes where the AP site is positioned opposite the 3' terminus of a complementary primer strand are incised with an efficiency similar (less than twofold difference) to that of the ssAP substrate alone. Moreover, Ape1 cleaved AP sites in fork-like and bubble DNA structures with an efficiency that is identical or up to sevenfold higher than ssAP-DNA. The findings here suggest that Ape1 ssAP and dsAP endonuclease activities are regulated by sequence context and the relative concentrations of certain chemical elements in vivo, and that Ape1 incision activity occurs on complex replication, recombination, and/or transcription DNA intermediates.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Wilson DM 3rddoi
10.1016/j.jmb.2004.11.028keywords:
subject
Has Abstractpub_date
2005-02-04 00:00:00pages
1003-14issue
5eissn
0022-2836issn
1089-8638pii
S0022-2836(04)01467-6journal_volume
345pub_type
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