Mammalian 5-Formyluracil−DNA Glycosylase. 1. Identification and Characterization of a Novel Activity That Releases 5-Formyluracil from DNA

Matsubara, Miyao; Masaoka, Aya; Tanaka, Tsubasa; Miyano, Takayuki; Kato, Nagisa; Terato, Hiroaki; Ohyama, Yoshihiko; Iwai, Shigenori; Ide, Hiroshi

doi:10.1021/bi027322v

Cited by 36 publications

(43 citation statements)

References 48 publications

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“…5C). The present results, together with those reported for mammalian NTH1 (16 -19), NEIL1 (14,(31)(32)(33)(34)(35)(36)(37), and SMUG1 (43,44), show an elaborate backup system of mammalian DNA glycosylases that work in the first step of BER for oxidatively damaged DNA. For example, at least two or three enzymes can participate in the repair of Tg and urea residues (NTH1 and NEIL1), hoU (SMUG1, NTH1, and NEIL1), and mFapyG and its unmethylated analogue (OGG1, NTH1, and NEIL1).…”

Section: Discussionsupporting

confidence: 84%

“…30UR containing a urea residue was prepared by mild alkaline treatment of 30TG5R and 30TG5S (18,41). 25FU, 25HMU, and 25OG containing 5-formyluracil (fU), 5-hydroxymethyluracil (hmU), and 7,8-dihydro-8-oxoguanine (8-oxoG), respectively, were chemically synthesized (42)(43)(44). 25HOU, 25HOC, 34FP, and 25OXA containing 5-hydroxyuracil (hoU), 5-hydroxycytosine (hoC), 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (mFapyG), and oxanine (Oxa), respectively, were prepared by DNA polymerase reactions with modified 2Ј-deoxynucleoside 5Ј-triphosphates as reported previously (19,(43)(44)(45).…”

Section: Methodsmentioning

confidence: 99%

“…25FU, 25HMU, and 25OG containing 5-formyluracil (fU), 5-hydroxymethyluracil (hmU), and 7,8-dihydro-8-oxoguanine (8-oxoG), respectively, were chemically synthesized (42)(43)(44). 25HOU, 25HOC, 34FP, and 25OXA containing 5-hydroxyuracil (hoU), 5-hydroxycytosine (hoC), 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (mFapyG), and oxanine (Oxa), respectively, were prepared by DNA polymerase reactions with modified 2Ј-deoxynucleoside 5Ј-triphosphates as reported previously (19,(43)(44)(45). The oligonucleotides containing the base lesions were 5Ј-end labeled with [␥- DNA Glycosylases-The purification of Endo III, Endo VIII, and hNTH1 were reported previously (19,43 …”

Section: Methodsmentioning

confidence: 99%

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

Katafuchi

Nakano

Masaoka

et al. 2004

Journal of Biological Chemistry

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118

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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 (1-3). 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 (4), and hence need to be restored by the cellular repair system (2, 3, 5). The major repair mechanism for such damage is the base excision repair (BER) 1 pathway (6), 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 (7,8). 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 ␤-elimination ...

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Section: Discussionsupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Katafuchi

Nakano

Masaoka

et al. 2004

Journal of Biological Chemistry

Self Cite

118

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“…Evidence in favor of this interpretation includes the demonstration that SMUG1 initiates BER by excision of 5-hydroxymethyluracil (5-OH-meU) adducts, which arises as a result of oxidation of thymine or oxidation and deamination of 5-methylcytosine. [22][23][24] UNG and SMUG1 and cancer. The UNG gene maps to chromosome 12q24.1, a region of the genome frequently lost in gastric carcinomas.…”

Section: Germline and Tumor-associated Variants Of Dna Glycosylases Mmentioning

confidence: 99%

Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

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“…Although hSMUG1 was originally characterized as a single strand selective glycosylase (13), more recent studies suggest it is more active on mispaired uracil in duplex DNA (14), and it has an extended substrate range, removing several oxidized pyrimidines (15)(16)(17)(18), including 5-hydroxymethyluracil (HmU), 5-formyluracil (FoU), and 5-hydroxyuracil (HoU). TDG appears to act exclusively on duplex substrates, with a strong preference for mispaired pyrimidines, including thymine, and a strong preference for damage located in CpG dinucleotides (19 -21).…”

mentioning

confidence: 99%

Mechanisms of Base Selection by Human Single-stranded Selective Monofunctional Uracil-DNA Glycosylase

Darwanto

Theruvathu

Sowers

et al. 2009

Journal of Biological Chemistry

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hSMUG1 (human single-stranded selective monofunctional uracil-DNA glyscosylase) is one of three glycosylases encoded within a small region of human chromosome 12. Those three glycosylases, UNG (uracil-DNA glycosylase), TDG (thymine-DNA glyscosylase), and hSMUG1, have in common the capacity to remove uracil from DNA. However, these glycosylases also repair other lesions and have distinct substrate preferences, indicating that they have potentially redundant but not overlapping physiological roles. The mechanisms by which these glycosylases locate and selectively remove target lesions are not well understood. In addition to uracil, hSMUG1 has been shown to remove some oxidized pyrimidines, suggesting a role in the repair of DNA oxidation damage. In this paper, we describe experiments in which a series of oligonucleotides containing purine and pyrimidine analogs have been used to probe mechanisms by which hSMUG1 distinguishes potential substrates. Our results indicate that the preference of hSMUG1 for mispaired uracil over uracil paired with adenine is best explained by the reduced stability of a duplex containing a mispair, consistent with previous reports with Escherichia coli mispaired uracil-DNA glycosylase. We have also extended the substrate range of hSMUG1 to include 5-carboxyuracil, the last in the series of damage products from thymine methyl group oxidation. The properties used by hSMUG1 to select damaged pyrimidines include the size and free energy of solvation of the 5-substituent but not electronic inductive properties. The observed distinct mechanisms of base selection demonstrated for members of the uracil glycosylase family help explain how considerable diversity in chemical lesion repair can be achieved.

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Mammalian 5-Formyluracil−DNA Glycosylase. 1. Identification and Characterization of a Novel Activity That Releases 5-Formyluracil from DNA

Cited by 36 publications

References 48 publications

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

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

Is Base Excision Repair a Tumor Suppressor Mechanism?

Mechanisms of Base Selection by Human Single-stranded Selective Monofunctional Uracil-DNA Glycosylase

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