Characterization of Escherichia coli Endonuclease VIII

Escherichia coli endonuclease VIII (endo VIII) was identified as an enzyme that, like endonuclease III (endo III), removes radiolysis products of thymine including thymine glycol, dihydrothymine, β-ureidoisobutyric acid, and urea from double-stranded plasmid or phage DNA and cleaves the DNA strand at abasic (AP) sites (Melamede, R. J., Hatahet, Z., Kow, Y. W., Ide., H., and Wallace, S. S. (1994) Biochemistry 33, 1255–1264). Using apparently homogeneous endo VIII protein, we now show that endo VIII removes from double-stranded oligodeoxyribonucleotides the stable oxidative products of cytosine, 5-hydroxycytosine and 5-hydroxyuracil. Endo VIII cleaved the damage-containing DNA strand by β,δ-elimination as does formamidopyrimidine DNA glycosylase (Fpg). Like Fpg, endo VIII also excised the 5′-terminal deoxyribose phosphate from an endonuclease IV (endo IV) pre-incised AP site. Thus, in addition to amino acid sequence homology (Jiang, D., Hatahet, Z., Blaisdell, J., Melamede, R. J., and Wallace, S. S. (1997) J. Bacteriol. 179, 3773–3782), endo VIII shares a number of catalytic properties with Fpg. In addition, endo VIII specifically bound to oligodeoxynucleotides containing a reduced AP site with a stoichiometry of 1:1 for protein to DNA with an apparent equilibrium dissociation constant of 3.9 nm. Like Fpg and endo III, the DNase I footprint was small with contact sites primarily on the damage-containing strand; unlike Fpg and endo III, the DNA binding of endo VIII to DNA was asymmetric, 3′ to the reduced AP site. Escherichia coli endonuclease VIII (endo VIII) was identified as an enzyme that, like endonuclease III (endo III), removes radiolysis products of thymine including thymine glycol, dihydrothymine, β-ureidoisobutyric acid, and urea from double-stranded plasmid or phage DNA and cleaves the DNA strand at abasic (AP) sites (Melamede, R. J., Hatahet, Z., Kow, Y. W., Ide., H., and Wallace, S. S. (1994) Biochemistry 33, 1255–1264). Using apparently homogeneous endo VIII protein, we now show that endo VIII removes from double-stranded oligodeoxyribonucleotides the stable oxidative products of cytosine, 5-hydroxycytosine and 5-hydroxyuracil. Endo VIII cleaved the damage-containing DNA strand by β,δ-elimination as does formamidopyrimidine DNA glycosylase (Fpg). Like Fpg, endo VIII also excised the 5′-terminal deoxyribose phosphate from an endonuclease IV (endo IV) pre-incised AP site. Thus, in addition to amino acid sequence homology (Jiang, D., Hatahet, Z., Blaisdell, J., Melamede, R. J., and Wallace, S. S. (1997) J. Bacteriol. 179, 3773–3782), endo VIII shares a number of catalytic properties with Fpg. In addition, endo VIII specifically bound to oligodeoxynucleotides containing a reduced AP site with a stoichiometry of 1:1 for protein to DNA with an apparent equilibrium dissociation constant of 3.9 nm. Like Fpg and endo III, the DNase I footprint was small with contact sites primarily on the damage-containing strand; unlike Fpg and endo III, the DNA binding of endo VIII to DNA was asymmetric, 3′ to the reduced AP site. Free radicals can be produced during normal cellular metabolism and after exposure to ionizing radiation, near UV light (320–380 nm), and chemical oxidants (for reviews see Refs. 1Cadenas E. Ahmad S. Oxidative Stress and Antioxidant Defenses in Biology. Chapman 32: 115-154Crossref PubMed Scopus (450) Google Scholar). Free radical-mediated damages are believed to be the most frequently occurring DNA damages and include modifications to the purine and pyrimidine bases, the deoxyribose sugar, as well as breaks in the phosphodiester backbone (for reviews see Refs. 2Hutchinson F. Prog. Nucleic Acid Res. Mol. Biol. 1985; 32: 115-154Crossref PubMed Scopus (450) Google Scholar and 3Breen A.P. Murphy J.A. Free Radical Biol. 18: 1033-1077Crossref PubMed Scopus (910) Google Scholar). Base excision repair is the major pathway that processes oxidative DNA lesions with Escherichia coli defining the prototypic enzymes. Three E. coli DNA N-glycosylases containing an associated AP lyase activity, formamidopyrimidine DNA glycosylase (Fpg) 1The abbreviations used are: Fpg, formamidopyrimidine DNA glycosylase; endo, endonuclease; Tg, thymine glycol; DHT, dihydrothymine; AP, abasic; redAP, reduced AP; 5-OHC, 5-hydroxycytosine; 5-OHU, 5-hydroxyuracil; Pol I, polymerase I; dRp, deoxyribose phosphate; ds, double-stranded; FAPY, formamidopyrimidine; dTgMP, thymidine glycol 5′-monophosphate; dDHTMP, dihydrothymidine 5′-monophosphate; 5-OHdCHP, 5-hydroxycytidine 5′-monophosphate; 5-OHdVMP, 5-hydroxyuridine 5′-monophosphate. 1The abbreviations used are: Fpg, formamidopyrimidine DNA glycosylase; endo, endonuclease; Tg, thymine glycol; DHT, dihydrothymine; AP, abasic; redAP, reduced AP; 5-OHC, 5-hydroxycytosine; 5-OHU, 5-hydroxyuracil; Pol I, polymerase I; dRp, deoxyribose phosphate; ds, double-stranded; FAPY, formamidopyrimidine; dTgMP, thymidine glycol 5′-monophosphate; dDHTMP, dihydrothymidine 5′-monophosphate; 5-OHdCHP, 5-hydroxycytidine 5′-monophosphate; 5-OHdVMP, 5-hydroxyuridine 5′-monophosphate., endonuclease III (endo III), and endonuclease VIII (endo VIII), have been reported to recognize and remove oxidative base lesions and subsequently cleave the phosphodiester backbone, initiating the repair process (for reviews see Refs. 4Demple B. Harrison L. Annu. Rev. Biochem. 1994; 63: 915-948Crossref PubMed Scopus (1282) Google Scholar and 5Wallace S.S. Scandalios J.G. Oxidative Stress and the Molecular Biology of Antioxidant Defenses. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1997: 49-90Google Scholar). Fpg and endo III have been well studied. Fpg, encoded by the fpg or mutM gene (6Boiteux S. O'Connor T.R. Laval J. EMBO J. 1987; 6: 3177-3183Crossref PubMed Scopus (250) Google Scholar, 7Cabrera M. Nghiem Y. Miller J. J. Bacteriol. 1988; 170: 5405-5407Crossref PubMed Google Scholar), was initially identified by its ability to recognize and excise from DNA 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (FAPY-guanine), the imidazole ring open form of N 7-methylguanine (8Chetsanga C.J. Lindahl T. Nucleic Acids Res. 1979; 6: 3673-3684Crossref PubMed Scopus (229) Google Scholar). Fpg also releases 4,6-diamino-5-formamidopyrimidine (FAPY-adenine) (9Breimer L.H. 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M.H. 1988; Scopus Google Scholar), is encoded by the gene R.P. B. Proc. Natl. Acad. Sci. U. S. A. 1985; PubMed Scopus Google Scholar). was initially identified by its endonuclease on Wallace S.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and DNA M. J. Biol. Chem. PubMed Google Scholar, S. J. Biol. Chem. PubMed Google Scholar). Endo III specifically removes radiolysis products of thymine including ring or ring lesions and glycol and urea (for reviews see Refs. 4Demple B. Harrison L. Annu. Rev. Biochem. 1994; 63: 915-948Crossref PubMed Scopus (1282) Google Scholar and 5Wallace S.S. Scandalios J.G. Oxidative Stress and the Molecular Biology of Antioxidant Defenses. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1997: 49-90Google Scholar). Endo III also 5-hydroxycytosine glycol, (11Hatahet Z. Kow Y.W. Purmal A.A. Cunningham R.P. Wallace S.S. J. Biol. Chem. 1994; 269: 18814-18820Abstract PubMed Google Scholar, M. Laval J. S. 32: PubMed Scopus Google Scholar), and J. 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A. 1985; PubMed Scopus Google Scholar). that for the of a in is the of a for the repair of base we identified a E. DNA endo that a to that of endo III Z. Kow Y.W. H. Wallace S.S. 1994; PubMed Scopus Google Scholar). Endo VIII and removes from DNA Tg, DHT, β-ureidoisobutyric acid, and urea and cleaves DNA containing an AP site Z. Kow Y.W. H. Wallace S.S. 1994; PubMed Scopus Google as a for a gene for endo was and are to the of and and a in Z. J. Wallace S.S. J. Bacteriol. PubMed Google Scholar). In we the of endo VIII and show that products in addition to thymine products and cleaves the DNA backbone a also that endo VIII a and show the and stoichiometry of endo VIII binding to DNA containing a reduced AP site. DNA coli DNA polymerase I, and from U. S. glycosylase was from E. coli endonuclease III was by of New at E. coli endonuclease IV and glycosylase in a to that for endo VIII Z. J. Wallace S.S. J. Bacteriol. PubMed Google Scholar). and from of was from and from from or J. T. in the of and Molecular at the of or from oligodeoxynucleotides on a containing of endo the oligodeoxynucleotides containing an AP site by a with E. coli glycosylase at for reduced AP site containing oligodeoxynucleotides by with in at for by and a of oligodeoxynucleotides containing an Tg, DHT, 5-OHC, or was by Z. Purmal A.A. Wallace S.S. Nucleic Acids Res. PubMed Scopus Google Scholar). dTgMP, dDHTMP, or was on to the 3′ of an with and the containing a base was on a of double-stranded was by with DNA of the containing a base with its after to the or by with E. coli DNA polymerase I of the containing a base after to a oligodeoxynucleotides used for the are in oligodeoxynucleotides by or by to a to form a double-stranded of endo VIII been reported Z. J. Wallace S.S. J. Bacteriol. PubMed Google Scholar). from an E. coli by with the was to and protein and an of reduced Endo VIII was by its ability to a double-stranded plasmid DNA in an protein of endo VIII was the of the as a In of endo as well as endo III, endo and Fpg, was as the of enzyme to cleave of double-stranded containing an AP site at apparently homogeneous endo VIII as by and protein sequence Z. J. Wallace S.S. J. Bacteriol. PubMed Google Scholar), was used in the of the a double-stranded was with of the enzyme in or of or at and endo III, Fpg, and endo IV used as in by of the and a containing with of to in acid, was at for and the DNA binding double-stranded or in was with of endo VIII in of at for the binding was with of the or with endo VIII for after to a on the a with of to and in and acid, at for at was and binding of endo VIII to the can be by equilibrium dissociation can be from the of endo VIII and endo at equilibrium from and is the of DNA and is the of protein at the apparent the of protein is to that of the protein the apparent of the is the apparent the of bound was the of endo was used to the of and the was Molecular was the of and Nucleic Acids Res. PubMed Scopus Google Scholar). after the DNA binding the was on by with the and including the and the and including the and the the with the containing the binding and the and the with the containing the and the was and the was with and of was and the of the of the endo and the to that of the and the to PubMed Scopus Google Scholar). of the the of the and the of was for the a from the of endo was from its in the containing a reduced AP site at from the was with endo VIII or Fpg protein, in the in the in at of DNase I was and at for was with and and the by Endo VIII was to specifically cleave plasmid or phage DNA containing AP β-ureidoisobutyric acid, DHT, or a and to and from and DNA by of the products Z. Kow Y.W. H. 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PubMed Scopus Google Scholar). of the 3′ phosphate was by the the endo VIII was by with the endo VIII be cleaved to by the of Pol I or with the addition of the to the of the by the polymerase of Pol I as is the containing a 3′ and the show that the 3′ and products of endo VIII at an AP site from the of endo VIII also as does Fpg O'Connor T. Laval J. Biochem. J. PubMed Scopus Google Scholar), a double-stranded with a strand was with endo III to by with endo that the of endo III be cleaved by endo a with a of endo VIII was used for of an products of as to the of endo III and the to the of Fpg that the by endo VIII of AP DNA from of the and that the can be also that, with a of endo VIII that to the strand was produced from of the endo with of from the was that of β,δ-elimination of the strand by a of endo VIII with Thus, endo VIII bound to or of the with a with the that, after endo VIII from the DNA or that endo VIII to its is that endo III bound to the cleaved endo VIII the of endo III used was well the IV Biochem. J. PubMed Scopus Google and III B. the New AP DNA to the AP site a 5′-terminal in the 3′ be by the to 3′ of DNA polymerase I at and protein and the of the is at F. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. J. Biol. Chem. PubMed Google Scholar, Lindahl T. 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PubMed Google and of lyase endo VIII was for in to by endo IV of a double-stranded at an AP site was by with of endo VIII Fpg as a the in was also by a for the 3′ of the the endo VIII was by with the with to the is and during in a at show that of endo VIII with the endo the of a that to with the produced by Fpg and with in the from the endo IV Fpg in as by the of endo of the 3′ excision was produced from the 3′ endo from endo VIII excision also to the from endo VIII of the and that of the containing a phosphate and with and with the 3′ from the endo IV endo VIII was to a with the as the 3′ from endo VIII and with and in was to be the form of the 3′ endo IV show that the 3′ from endo VIII excision of the endo and that from the endo VIII of the and a with an AP site in a sequence Thus, endo VIII was to remove a from the 3′ by endo IV at an AP site. endo III also excised the with a endo VIII or Fpg of endo III also been by Laval J. O'Connor T.R. J. Biol. Chem. PubMed Google Scholar). endo VIII to a DNA during endo VIII Z. J. Wallace S.S. J. Bacteriol. PubMed Google Scholar), oligodeoxynucleotides to the DNA binding and of endo VIII by the binding also for of endo show of DNA binding of endo double-stranded containing a redAP, or thymine was with of endo of the with of endo VIII produced of a with reduced an endo of endo VIII with the or produced of the at endo VIII that endo VIII specifically bound to binding of endo VIII to double-stranded DNA was by binding of was well with of or with a of endo VIII can be the at a to and that of the DNA the and with In of the I was a of the DNA was with binding of endo VIII to DNA was also with of oligodeoxynucleotides the was in a sequence was also by the DNA with endo VIII for by with of the DNA for the as the apparent equilibrium dissociation for the binding of endo VIII to the the of in the of was a of the endo the of endo from the for the was to be 3.9 the binding of endo VIII to the the stoichiometry of the endo was by the of and Nucleic Acids Res. PubMed Scopus Google Scholar). of the binding in a of of by with protein of of the protein and the endo and for the as in A. a PubMed Scopus Google was by the of the for the a for the the of endo was to be the of the was the of endo VIII in was is in with the of endo VIII protein we that the stoichiometry of the endo was 1:1 for endo In an to the contact sites endo VIII and the reduced DNase I footprint was that the footprint of endo VIII on the damage-containing strand of the is with to 3′ to the abasic site. DNase sites also at and to the reduced AP site with an contact at the and base to the reduced abasic site. In sequence a DNase I at In the DNase I footprint of Fpg protein on the reduced was with 3′ and to the Fpg DNase I footprint is with the footprint of Fpg protein on DNA containing a the binding was a of on of the J. Miller Grollman A.P. J. Biol. Chem. PubMed Google Scholar). to be by endo VIII of a on the strand with a DNase I does that endo VIII to the the footprint was protein and with a reduced AP site in sequence Endo VIII is the E. coli DNA in addition to endo III and Fpg, been to recognize and remove oxidative DNA base lesions Z. Kow Y.W. H. Wallace S.S. 1994; PubMed Scopus Google Scholar). of III and VIII to be recognize thymine ring products (for reviews see Refs. J. Kasai H. Shibutani S. Chung M.H. Laval J. Grollman A.P. Nishimura S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4690-4694Crossref PubMed Scopus (690) Google Scholar and Z. Kow Y.W. Purmal A.A. Cunningham R.P. Wallace S.S. J. Biol. Chem. 1994; 269: 18814-18820Abstract PubMed Google Scholar), products with ring urea Z. Kow Y.W. H. Wallace S.S. 1994; PubMed Scopus Google Scholar), and AP sites in that in the endo VIII and endo III to the of are produced by ionizing radiation, as well as normal cellular is by of the of endo VIII endo III Z. J. Wallace S.S. J. 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