Differential Specificity of Human and Escherichia coli Endonuclease III and VIII Homologues for Oxidative Base Lesions

In human cells, oxidative pyrimidine lesions are restored by the base excision repair pathway initiated by homologues of Endo III (hNTH1) and Endo VIII (hNEIL1 and hNEIL2). In this study we have quantitatively analyzed and compared their activity toward nine oxidative base lesions and an apurinic/apyrimidinic (AP) site using defined oligonucleotide substrates. hNTH1 and hNEIL1 but not hNEIL2 excised the two stereoisomers of thymine glycol (5R-Tg and 5S-Tg), but their isomer specificity was markedly different: the relative activity for 5R-Tg:5S-Tg was 13:1 for hNTH1 and 1.5:1 for hNEIL1. This was also the case for their Escherichia coli homologues: the relative activity for 5R-Tg:5S-Tg was 1:2.5 for Endo III and 3.2:1 for Endo VIII. Among other tested lesions for hNTH1, an AP site was a significantly better substrate than urea, 5-hydroxyuracil (hoU), and guanine-derived formamidopyrimidine (mFapyG), whereas for hNEIL1 these base lesions and an AP site were comparable substrates. In contrast, hNEIL2 recognized an AP site exclusively, and the activity for hoU and mFapyG was marginal. hNEIL1, hNEIL2, and Endo VIII but not hNTH1 and Endo III formed cross-links to oxanine, suggesting conservation of the -fold of the active site of the Endo VIII homologues. The profiles of the excision of the Tg isomers with HeLa and E. coli cell extracts closely resembled those of hNTH1 and Endo III, confirming their major contribution to the repair of Tg isomers in cells. However, detailed analysis of the cellular activity suggests that hNEIL1 has a significant role in the repair of 5S-Tg in human cells. In human cells, oxidative pyrimidine lesions are restored by the base excision repair pathway initiated by homologues of Endo III (hNTH1) and Endo VIII (hNEIL1 and hNEIL2). In this study we have quantitatively analyzed and compared their activity toward nine oxidative base lesions and an apurinic/apyrimidinic (AP) site using defined oligonucleotide substrates. hNTH1 and hNEIL1 but not hNEIL2 excised the two stereoisomers of thymine glycol (5R-Tg and 5S-Tg), but their isomer specificity was markedly different: the relative activity for 5R-Tg:5S-Tg was 13:1 for hNTH1 and 1.5:1 for hNEIL1. This was also the case for their Escherichia coli homologues: the relative activity for 5R-Tg:5S-Tg was 1:2.5 for Endo III and 3.2:1 for Endo VIII. Among other tested lesions for hNTH1, an AP site was a significantly better substrate than urea, 5-hydroxyuracil (hoU), and guanine-derived formamidopyrimidine (mFapyG), whereas for hNEIL1 these base lesions and an AP site were comparable substrates. In contrast, hNEIL2 recognized an AP site exclusively, and the activity for hoU and mFapyG was marginal. hNEIL1, hNEIL2, and Endo VIII but not hNTH1 and Endo III formed cross-links to oxanine, suggesting conservation of the -fold of the active site of the Endo VIII homologues. The profiles of the excision of the Tg isomers with HeLa and E. coli cell extracts closely resembled those of hNTH1 and Endo III, confirming their major contribution to the repair of Tg isomers in cells. However, detailed analysis of the cellular activity suggests that hNEIL1 has a significant role in the repair of 5S-Tg in human cells. DNA carrying vital genetic information of cells constantly suffers from spontaneous deamination and depurination, alkylation, and oxidation (1Lindahl T. Nature. 1993; 362: 709-715Google Scholar, 2Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D. C.1995Google Scholar, 3Friedberg E.C. Nature. 2003; 421: 436-440Google Scholar). These reactions lead to modifications of the DNA backbone and bases, with the latter predominating. The resulting aberrant bases are potentially genotoxic because of the loss or alteration of base pairing information (4Kunkel T.A. Bebenek K. Annu. Rev. Biochem. 2000; 69: 497-529Google Scholar), and hence need to be restored by the cellular repair system (2Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D. C.1995Google Scholar, 3Friedberg E.C. Nature. 2003; 421: 436-440Google Scholar, 5Lindahl T. Wood R.D. Science. 1999; 286: 1897-1905Google Scholar). The major repair mechanism for such damage is the base excision repair (BER) 1The abbreviations used are: BER, base excision repair; Endo, endonuclease; hNTH1, human Nth homologue; hNEIL1 and hNEIL2, human Nei-like 1 and 2; Tg, thymine glycol; hoU, 5-hydroxyuracil; hoC, 5-hydroxycytosine; fU, 5-formyluracil; hmU, 5-hydroxymethyluracil; AP, apurinic/apyrimidinic site; 8-oxoG, 7,8-dihydro-8-oxoguanine; mFapyG, 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine; Oxa, oxanine; BSA, bovine serum albumin. 1The abbreviations used are: BER, base excision repair; Endo, endonuclease; hNTH1, human Nth homologue; hNEIL1 and hNEIL2, human Nei-like 1 and 2; Tg, thymine glycol; hoU, 5-hydroxyuracil; hoC, 5-hydroxycytosine; fU, 5-formyluracil; hmU, 5-hydroxymethyluracil; AP, apurinic/apyrimidinic site; 8-oxoG, 7,8-dihydro-8-oxoguanine; mFapyG, 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine; Oxa, oxanine; BSA, bovine serum albumin. pathway (6Scharer O.D. Jiricny J. Bioessays. 2001; 23: 270-281Google Scholar), which is conserved from bacteria to humans. In the first step of BER, DNA glycosylases with distinct damage specificities detect the aberrant base in the vast sea of normal bases and remove it from the DNA backbone, leaving an apurinic/apyrimidinic (AP) site. The resulting AP site is further processed and repaired by the subsequent action of AP endonuclease (Endo), DNA polymerase, and DNA ligase through the short patch or long patch BER pathway. The initial search for DNA glycosylases involved in the repair of oxidatively damaged bases in Escherichia coli identified Endo III, Endo VIII, and formamidopyrimidine-DNA glycosylase (7Wallace S.S. Free Radic. Biol. Med. 2002; 33: 1-14Google Scholar, 8Gros L. Saparbaev M.K. Laval J. Oncogene. 2002; 21: 8905-8925Google Scholar). The principal substrates of Endo III and Endo VIII are oxidative pyrimidine lesions. They exhibit redundant damage specificity and catalyze the hydrolysis of the N-glycosidic bond (N-glycosylase activity) and the subsequent incision of an AP site by AP lyase activity via β-elimination (Endo III) or β,δ-elimination (Endo VIII). The E. coli mutants deficient in both Endo III and Endo VIII are strong spontaneous mutators (9Jiang D. Hatahet Z. Blaisdell J.O. Melamede R.J. Wallace S.S. J. Bacteriol. 1997; 179: 3773-3782Google Scholar, 10Blaisdell J.O. Hatahet Z. Wallace S.S. J. Bacteriol. 1999; 181: 6396-6402Google Scholar) and hypersensitive to the agents that generate reactive oxygen species such as ionizing radiation and hydrogen peroxide (9Jiang D. Hatahet Z. Blaisdell J.O. Melamede R.J. Wallace S.S. J. Bacteriol. 1997; 179: 3773-3782Google Scholar, 11Saito Y. Uraki F. Nakajima S. Asaeda A. Ono K. Kubo K. Yamamoto K. J. Bacteriol. 1997; 179: 3783-3785Google Scholar). The principal substrates of formamidopyrimidine-DNA glycosylase are oxidative purine lesions, and it exhibits N-glycosylase and β,δ-AP lyase activities. The E. coli mutants deficient in formamidopyrimidine-DNA glycosylase are not sensitive to ionizing radiation but exhibit a mild spontaneous mutator phenotype (12Cabrera M. Nghiem Y. Miller J.H. J. Bacteriol. 1988; 170: 5405-5407Google Scholar, 13Michaels M.L. Cruz C. Grollman A.P. Miller J.H. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7022-7025Google Scholar). Interestingly, while showing distinct substrate specificity, Endo VIII and formamidopyrimidine-DNA glycosylase belong to the same structural family, the Endo VIII/formamidopyrimidine-DNA glycosylase superfamily (14Wallace S.S. Bandaru V. Kathe S.D. Bond J.P. DNA Repair (Amst.). 2003; 2: 441-453Google Scholar, 15Zharkov D.O. Shoham G. Grollman A.P. DNA Repair (Amst.). 2003; 2: 839-862Google Scholar). The mammalian Endo III homologue (NTH1) and a functional homologue of formamidopyrimidine-DNA glycosylase (OGG1) have been identified previously, and their functions in BER have been assessed using purified proteins (16Ikeda S. Biswas T. Roy R. Izumi T. Boldogh I. Kurosky A. Sarker A.H. Seki S. Mitra S. J. Biol. Chem. 1998; 273: 21585-21593Google Scholar, 17Dizdaroglu M. Karahalil B. Senturker S. Buckley T.J. Roldan-Arjona T. Biochemistry. 1999; 38: 243-246Google Scholar, 18Asagoshi K. Odawara H. Nakano H. Miyano T. H. Y. Seki S. H. Biochemistry. 2000; Scholar, K. T. Y. H. Y. Seki S. H. J. Biol. Chem. 2000; Scholar, C. J.P. M. S. 1999; Scholar, K. T. H. Y. Y. T. S. H. T. H. J. Biol. Chem. 2000; Scholar, D.O. T.A. Grollman A.P. J. Biol. Chem. 2000; Scholar), M. S. T. R. H. S. Sarker A.H. Seki S. M. K. J. M. J.H. G. A. J. 2002; 21: Scholar, W. M.K. A. R.J. Biol. 2002; Scholar, B. J. Biol. Chem. 2003; Scholar, A. I. S. E. G. B. E. T. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar, T. M. Y. S. M. M. H. Y. H. K. T. S. T. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar, T. K. T. S. 2003; Scholar), and analysis S.D. Nature. 2000; Scholar, S.D. W. M. Biol. 2003; Scholar). has been that have Endo VIII homologues V. S. Wallace S.S. Bond J.P. DNA Repair (Amst.). 2002; Scholar, Izumi T. Boldogh I. B. M. Mitra S. Proc. Natl. Acad. Sci. U. S. A. 2002; are and the conserved of DNA glycosylases involved in the repair of oxidatively damaged pyrimidine and purine lesions. the repair of the mammalian Endo VIII homologues that Endo III and Endo VIII, and not redundant damage specificity and oxidative pyrimidine lesions (14Wallace S.S. Bandaru V. Kathe S.D. Bond J.P. DNA Repair (Amst.). 2003; 2: 441-453Google Scholar, V. S. Wallace S.S. Bond J.P. DNA Repair (Amst.). 2002; Scholar, Izumi T. Boldogh I. B. M. Mitra S. Proc. Natl. Acad. Sci. U. S. A. 2002; Scholar, Hatahet Z. B. Boldogh I. Mitra S. Izumi T. J. Biol. Chem. 2002; Scholar, M. S. K. S. A. J. Biol. Chem. 2002; Scholar, I. V. L. T. M. E. 2002; Scholar, T.A. E. D.O. Miller H. Grollman A.P. DNA Repair (Amst.). 2003; 2: Scholar, H. Mitra S. J. Biol. Chem. 2003; Scholar). However, their toward base lesions have been assessed using substrates with or and of DNA and of damaged the of activity In of this we and quantitatively compared the activity of human and hNEIL1, and and that of their E. coli homologues (Endo III and Endo using oligonucleotide substrates. that hNTH1, hNEIL1, and hNEIL2 exhibit significantly toward the stereoisomers of thymine glycol and other oxidative base lesions, and that this is also the case for Endo III and Endo VIII. These with those from cell that base lesions by reactive oxygen species are from DNA distinct in cells, and hence that their genotoxic be in with their repair substrates used in this study are in I. and the and were using the as S. Chem. 2000; Scholar, S. Chem. J. 2001; Scholar). Tg has with to the and two and and two and The of isomers is in because of in and is the of isomers J. R.J. 1992; Scholar). the of isomers are as and the of isomers as 5S-Tg this a was by mild of and K. Odawara H. Nakano H. Miyano T. H. Y. Seki S. H. Biochemistry. 2000; Scholar, H. Wallace S.S. Scholar). and and were A. H. M. Y. H. J. Biol. Chem. 2001; Scholar, M. A. T. Miyano T. H. Y. S. H. Biochemistry. 2003; Scholar, A. M. R. T. S. H. Y. A. H. Biochemistry. 2003; Scholar). and 5-hydroxyuracil (hoU), (mFapyG), and were by DNA reactions with as K. T. Y. H. Y. Seki S. H. J. Biol. Chem. 2000; Scholar, M. A. T. Miyano T. H. Y. S. H. Biochemistry. 2003; Scholar, A. M. R. T. S. H. Y. A. H. Biochemistry. 2003; Scholar, T. H. K. A. M. Y. T. K. H. J. Biol. Chem. 2003; Scholar). The the base lesions were with and and purified by a The were to and used for activity substrates are as the of an oligonucleotide the and the base it the the of a oligonucleotide the of the AP site was with glycosylase substrates used in this and the base the damage in substrates. The of the was the same as the for and the base the damage in substrates. The of the was the same as the for in a DNA of Endo III, Endo VIII, and hNTH1 were K. T. Y. H. Y. Seki S. H. J. Biol. Chem. 2000; Scholar, M. A. T. Miyano T. H. Y. S. H. Biochemistry. 2003; Scholar). The of hNEIL1 and hNEIL2 proteins were purified as V. S. Wallace S.S. Bond J.P. DNA Repair (Amst.). 2002; Scholar, Izumi T. Boldogh I. B. M. Mitra S. Proc. Natl. Acad. Sci. U. S. A. 2002; Scholar), hNEIL1 and hNEIL2 were from the human using the The DNA were the site of The for hNEIL1 and hNEIL2 were and E. coli was with or The of the was by and from the E. coli or was in and the of 1 the cell was for The were or cells were by The cell was and proteins in the were by The hNEIL1 was purified by and from The hNEIL2 was purified by and The hNEIL1 or hNEIL2 was 1 1 and and or The was with the using as a extracts were or The HeLa cell was from cells. The cell was in of 1 1 and 1 The cells were with of a and for The proteins in the were by The proteins were in 1 and 1 the same and used for activity The E. coli cell was from E. coli The cell was in of 1 1 and and to for The cells were by The cell was and the was used for activity The was with the substrates were with DNA glycosylases in for The of proteins was the activity of and is in the The used for with Endo III, Endo VIII, and hNEIL1 was 1 and The for hNTH1 was and BSA, and that for hNEIL2 was 1 and The was by the of and for were by and the in the was analyzed a with the cell the substrates and both were with the E. coli or HeLa cell extracts in 1 and for or coli were analyzed as for purified DNA reactions were to those for the activity using as a substrate and Endo VIII, hNEIL1, and hNEIL2 as In the for Endo VIII and hNEIL1, was by and for hNEIL2, was by The was for the was with and and by and of the were as with of was with hNEIL1 or hNEIL2 in the activity for to 1 The was with and by of hNEIL1 and hNEIL1 and hNEIL2 proteins were in E. coli and purified by analysis of the purified hNEIL1 a with the V. S. Wallace S.S. Bond J.P. DNA Repair (Amst.). 2002; Scholar, Izumi T. Boldogh I. B. M. Mitra S. Proc. Natl. Acad. Sci. U. S. A. 2002; Scholar). The purified hNEIL2 also a but was comparable with that of a The of the hNEIL2 in with the Hatahet Z. B. Boldogh I. Mitra S. Izumi T. J. Biol. Chem. 2002; Scholar). were that the of Endo III or Endo VIII from the E. coli hNEIL1 and hNEIL2 were with an AP site in the of and the base formed DNA and was analyzed by hNEIL1 and hNEIL2 to a which than that formed with Endo VIII This further that the hNEIL1 and hNEIL2 were from Endo VIII and Endo III of for Tg hNEIL1, hNEIL2, and their E. coli homologues (Endo III and Endo were with and and and the were analyzed by of the of of two that of used for the which was the hNTH1 and hNEIL1 recognized both and 5S-Tg but their specificity for the isomers hNTH1 excised compared with 5S-Tg whereas hNEIL1 excised better than 5S-Tg and 5S-Tg in and were to by mild hNTH1 and hNEIL1 the same activity toward from the two Tg isomers not These that the specificities of hNTH1 and hNEIL1 toward the Tg isomers from the distinct and of the pyrimidine The activity of hNEIL2 for the Tg isomers was the the of the of the in the activity for the two Tg isomers was as the and is in to the in the specificity toward 5S-Tg is 13:1 for hNTH1 and 1.5:1 for hNEIL1 in the isomer specificity hNTH1 and hNEIL1. also be from the activity that for hNTH1 exhibits a than hNEIL1 whereas for hNEIL1 exhibits a than hNTH1 These are in to those for and T.A. E. D.O. Miller H. Grollman A.P. DNA Repair (Amst.). 2003; 2: Scholar), the isomer specificities of and for the two Tg isomers are to those for hNTH1 and hNEIL1 in this The of the for from the is and that for 5S-Tg is that is an as compared with for both Tg which was not the case for hNEIL1 of Endo III and Endo VIII homologues for the and 5S-Tg The of was by the analysis as in and is the of used for the of two The used is of Endo III and Endo VIII homologues for oxidative base activity was not activity was not in a The activity of E. coli Endo III and Endo VIII for the two Tg isomers was in a and hNTH1 and hNEIL1, Endo III and Endo VIII significantly specificity for the two However, Endo III excised 5S-Tg better than and the specificity toward 5S-Tg was 1:2.5 hNTH1 and Endo III have an for the Tg Endo VIII excised as compared with 5S-Tg and the specificity toward 5S-Tg was 3.2:1 hNEIL1 has a of the in the isomer specificity of Endo VIII is than that of hNEIL1 is from the activity that Endo III exhibits than Endo VIII for both and 5S-Tg of for hNEIL1, hNEIL2, Endo III, and Endo VIII were with the substrates hoU mFapyG an AP site a and and were analyzed by not of the of of two that of used for the these the activity of the toward the lesions was as for the Tg isomers The activity for the lesions to that for an AP site is in with that for the Tg hNEIL1 comparable or better for urea, hoU, and mFapyG than for an AP site and was a substrate of hNEIL1, with the activity for this of that for the substrate of hNEIL1. fU, hmU, and were substrates than and hence the for these lesions were with a Hatahet Z. B. Boldogh I. Mitra S. Izumi T. J. Biol. Chem. 2002; Scholar), hNEIL2 significant activity for AP which was comparable with that of hNEIL1 (hNEIL1 and hNEIL2 The incision of an AP site by hNEIL2 was a of β,δ-elimination whereas that by hNEIL1 was a β,δ-elimination not hNEIL2 recognized hoU and mFapyG, the for these lesions were of that for an AP site and the of that was to the activity of hNEIL2 Hatahet Z. B. Boldogh I. Mitra S. Izumi T. J. Biol. Chem. 2002; Scholar), but significant was the The damage specificity of hNTH1 was from that of hNEIL1 hNEIL1, hNTH1 a toward an AP site the base lesions. The relative activity for the tested lesions in was AP mFapyG hoU 5S-Tg of the damage specificity of human and E. coli Endo III and Endo VIII homologues. the for base lesions in were to that for an AP and are the lesions. The used is to the of base lesions relative to an AP Endo VIII specificity to that of human homologue hNEIL1 and as was the case for Endo III and hNTH1 In was a substrate not for the human hNEIL1, and but also for the E. coli (Endo III and Endo VIII). the activity of human and and E. coli homologues (Endo III and Endo was the activity for mFapyG, which was a to substrate for hNTH1 and hNEIL1 but not for Endo III and Endo VIII. This is with for Endo III, and Endo VIII K. T. Y. H. Y. Seki S. H. J. Biol. Chem. 2000; Scholar). of for Tg substrates and 5S-Tg were with the extracts from HeLa and E. coli cells, and were analyzed by and and are of the of that of the cell used for the The HeLa cell excised compared with The profiles of the excision of the two Tg isomers with the HeLa cell closely resembled that with hNTH1 In contrast, the E. coli cell excised 5S-Tg as compared with The profiles of the excision of the two Tg isomers with the E. coli cell were to that with Endo III The detailed analysis of the cellular activity for the Tg with and hNEIL2 were with for to 1 and were analyzed by hNEIL1 and hNEIL2 not from DNA not both were to Oxa, resulting in in the Endo VIII but not Endo III and hNTH1 was with these T. H. K. A. M. Y. T. K. H. J. Biol. Chem. 2003; Scholar) not a of the active site in human and E. coli Endo VIII homologues hNEIL2, and Endo VIII). In this study we have that hNTH1, hNEIL1, and hNEIL2 exhibit quantitatively specificities toward oxidatively damaged bases and AP hNTH1 and hNEIL1 recognized both oxidatively damaged bases and AP showing a redundant of damage However, the specificity toward the lesions significantly hNTH1 and hNEIL1 and This was also the case for their E. coli homologues (Endo III and Endo VIII, and In contrast, hNEIL2 recognized AP exclusively, and the excision for the oxidatively damaged bases and was The with those for mammalian (16Ikeda S. Biswas T. Roy R. Izumi T. Boldogh I. Kurosky A. Sarker A.H. Seki S. Mitra S. J. Biol. Chem. 1998; 273: 21585-21593Google Scholar, 17Dizdaroglu M. Karahalil B. Senturker S. Buckley T.J. Roldan-Arjona T. Biochemistry. 1999; 38: 243-246Google Scholar, 18Asagoshi K. Odawara H. Nakano H. Miyano T. H. Y. Seki S. H. Biochemistry. 2000; Scholar, K. T. Y. H. Y. Seki S. H. J. Biol. Chem. 2000; Scholar), (14Wallace S.S. Bandaru V. Kathe S.D. Bond J.P. DNA Repair (Amst.). 2003; 2: 441-453Google Scholar, V. S. Wallace S.S. Bond J.P. DNA Repair (Amst.). 2002; Scholar, Izumi T. Boldogh I. B. M. Mitra S. Proc. Natl. Acad. Sci. U. S. A. 2002; Scholar, Hatahet Z. B. Boldogh I. Mitra S. Izumi T. J. Biol. Chem. 2002; Scholar, M. S. K. S. A. J. Biol. Chem. 2002; Scholar, I. V. L. T. M. E. 2002; Scholar, T.A. E. D.O. Miller H. Grollman A.P. DNA Repair (Amst.). 2003; 2: Scholar, H. Mitra S. J. Biol. Chem. 2003; Scholar), and M. A. T. Miyano T. H. Y. S. H. Biochemistry. 2003; Scholar, A. M. R. T. S. H. Y. A. H. Biochemistry. 2003; Scholar), an system of mammalian DNA glycosylases that in the first step of BER for oxidatively damaged two or in the repair of Tg and and hoU and and mFapyG and and This the of of M. S. T. R. H. S. Sarker A.H. Seki S. M. K. J. M. J.H. G. A. J. 2002; 21: Scholar, W. M.K. A. R.J. Biol. 2002; Scholar). The repair of hNEIL2 in BER to be further assessed because it hoU and mFapyG with In hNEIL1 and hNEIL2 oxidative base lesions in and DNA suggesting their repair role DNA M. S. K. S. A. J. Biol. Chem. 2002; Scholar, H. Mitra S. J. Biol. Chem. 2003; Scholar). Interestingly, the two Tg isomers were excised from DNA with by both HeLa and E. coli cell and the specificity for the isomers was HeLa and E. coli cells and is that ionizing radiation the two Tg isomers comparable G. A. K. A. L. J. Free Radic. 2: Scholar). the that the isomer is from DNA in human cells, whereas the 5S-Tg isomer is in E. coli cells. The and 5S-Tg isomers a DNA S. Chem. J. 2001; Scholar) and strong to DNA by R. C. S. F. Biochemistry. 2002; Scholar). However, with is than that 5S-Tg R. C. S. F. Biochemistry. 2002; Scholar). 5S-Tg is a as as than because of and for and a for mammalian cells. to be the two isomers have distinct other such as DNA by other and or and also the excision of a Tg isomer in distinct The profiles of the excision of the Tg isomers with the HeLa and E. coli cell extracts closely resembled those of hNTH1 and Endo III suggesting their major contribution to the cellular activity to This is also with the that the activity for by oxidation of with or in cells deficient in or Endo III coli is of the cells (9Jiang D. Hatahet Z. Blaisdell J.O. Melamede R.J. Wallace S.S. J. Bacteriol. 1997; 179: 3773-3782Google Scholar, M. S. T. R. H. S. Sarker A.H. Seki S. M. K. J. M. J.H. G. A. J. 2002; 21: Scholar, R.J. Hatahet Z. H. Wallace S.S. Biochemistry. 33: Scholar) not that the activity for is to and Endo VIII in mammalian and E. coli cells, the contribution of the to the excision of 5S-Tg in cells be using their activity for the 5S-Tg and isomers and cellular activity for the isomer The contribution of hNTH1 to the excision of 5S-Tg is and that of hNEIL1 is active of hNEIL1 in the repair of 5S-Tg in human cells. This is because of the of hNEIL1 for 5S-Tg than that of for the E. coli in III) that Endo III to the repair of 5S-Tg relative to Endo VIII in E. coli cells. The distinct of hNEIL1 and Endo VIII to the repair of the 5S-Tg isomer with the of the β,δ-elimination of with the HeLa cell and of Endo with the E. coli cell for 5S-Tg in and of Endo III and Endo VIII homologues to the excision of Tg isomers and in activity of purified for and isomers from the in for of for and for the mammalian and of for Endo III and Endo for the E. coli contribution of to the excision of was from the with or E. coli mutants The activity of purified for and isomers from the in for of for and for the mammalian and of for Endo III and Endo for the E. coli The contribution of to the excision of was from the with or E. coli mutants in a have that Oxa, a major by the with or T. T. M. H. K. J. Chem. Scholar, T. H. M. Endo K. K. T. K. 2000; Scholar), cross-links with proteins such as and DNA glycosylases T. H. K. A. M. Y. T. K. H. J. Biol. Chem. 2003; Scholar). The with and proteins is a of but that with DNA glycosylases is in than an and the of in DNA with the active site of DNA glycosylases to or Interestingly, for oxidative pyrimidine lesions, Endo VIII but not Endo III and hNTH1 are to T. H. K. A. M. Y. T. K. H. J. Biol. Chem. 2003; Scholar). is a but to the of the active site of DNA The study has that hNEIL1 and hNEIL2 cross-links to comparable with that of Endo VIII exhibit N-glycosylase activity toward This suggests that hNEIL1, hNEIL2, and Endo VIII in the -fold of the active which is distinct from that of Endo III and to Endo VIII Izumi T. R. M. Mitra S. J. Biol. Chem. 2000; Scholar, H. A. K. A. Y. T. M. K. Yamamoto K. H. 2002; Scholar), hNEIL1 and hNEIL2 are to have a to of purine lesions, but not of are The of the of hNEIL1 and hNEIL2 and their to those of Endo VIII D.O. G. R. J.H. Grollman A.P. Shoham G. J. 2002; 21: Scholar), Endo III Science. 1992; Scholar, J. 2003; Scholar), and hNTH1 further the the of oxidatively damaged bases by these the of the of this two showing the specificity of Endo III and Endo VIII homologues toward the Tg isomers in H. E. M. Grollman A.P. Scholar, T.A. DNA Repair (Amst.). Scholar). and for in the and of hNEIL1 and

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