Repair of oligodeoxyribonucleotides by O(6)-alkylguanine-DNA alkyltransferase.
Identifieur interne : 003315 ( Main/Exploration ); précédent : 003314; suivant : 003316Repair of oligodeoxyribonucleotides by O(6)-alkylguanine-DNA alkyltransferase.
Auteurs : Kieu X. Luu [États-Unis] ; Sreenivas Kanugula ; Anthony E. Pegg ; Gary T. Pauly ; Robert C. MoschelSource :
- Biochemistry [ 0006-2960 ] ; 2002.
Descripteurs français
- KwdFr :
- Animaux, Cinétique, Crotalus, Escherichia coli (enzymologie), Mutagenèse dirigée, O(6)-methylguanine-DNA methyltransferase (métabolisme), Oligodésoxyribonucléotides (métabolisme), Phosphatase alcaline (métabolisme), Phosphodiesterase I, Phosphodiesterases, Protéines recombinantes (métabolisme), Réparation de l'ADN, Spectroscopie par résonance magnétique, Spécificité du substrat, Substitution d'acide aminé, Séquence nucléotidique.
- MESH :
- enzymologie : Escherichia coli.
- métabolisme : O(6)-methylguanine-DNA methyltransferase, Oligodésoxyribonucléotides, Phosphatase alcaline, Protéines recombinantes.
- Animaux, Cinétique, Crotalus, Mutagenèse dirigée, Phosphodiesterase I, Phosphodiesterases, Réparation de l'ADN, Spectroscopie par résonance magnétique, Spécificité du substrat, Substitution d'acide aminé, Séquence nucléotidique.
English descriptors
- KwdEn :
- Alkaline Phosphatase (metabolism), Amino Acid Substitution, Animals, Base Sequence, Crotalus, DNA Repair, Escherichia coli (enzymology), Kinetics, Magnetic Resonance Spectroscopy, Mutagenesis, Site-Directed, O(6)-Methylguanine-DNA Methyltransferase (metabolism), Oligodeoxyribonucleotides (metabolism), Phosphodiesterase I, Phosphoric Diester Hydrolases, Recombinant Proteins (metabolism), Substrate Specificity.
- MESH :
- chemical , metabolism : Alkaline Phosphatase, O(6)-Methylguanine-DNA Methyltransferase, Oligodeoxyribonucleotides, Recombinant Proteins.
- enzymology : Escherichia coli.
- Amino Acid Substitution, Animals, Base Sequence, Crotalus, DNA Repair, Kinetics, Magnetic Resonance Spectroscopy, Mutagenesis, Site-Directed, Phosphodiesterase I, Phosphoric Diester Hydrolases, Substrate Specificity.
Abstract
Activity of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) is an important source of tumor cell resistance to alkylating agents. AGT inhibitors may prove useful in enhancing chemotherapy. AGT is inactivated by reacting stoichiometrically with O(6)-benzylguanine (b(6)G), which is currently in clinical trials for this purpose. Short oligodeoxyribonucleotides containing a central b(6)G are more potent inactivators of AGT than b(6)G. We examined whether human AGT could react with oligodeoxyribonucleotides containing multiple b(6)G residues. The single-stranded 7-mer 5'-d[T(b(6)G)(5)G]-3' was an excellent AGT substrate with all five b(6)G adducts repaired although one adduct was repaired much more slowly. The highly b(6)G-resistant Y158H and P140K AGT mutants were also inactivated by 5'-d[T(b(6)G)(5)G]-3'. Studies with 7-mers containing a single b(6)G adduct showed that 5'-d[TGGGG(b(6)G)G]-3' was more poorly repaired by wild-type AGT than 5'-d[T(b(6)G)GGGGG]-3' and 5'-d[TGG(b(6)G)GGG]-3' and was even less repairable by mutants Y158H and P140K. This positional effect was unaffected by interchanging the terminal 5'- or 3'-nucleotides and was also observed with single-stranded 16-mer oligodeoxyribonucleotides containing O(6)-methylguanine, where a minimum of four nucleotides 3' to the lesion was required for the most efficient repair. Annealing with the reverse complementary strands to produce double-stranded substrates increased the ability of AGT to repair adducts at all positions except at positions 2 and 15. Our results suggest that AGT recognizes the polarity of single-stranded DNA, with the best substrates having an adduct adjacent to the 5'-terminal residue. These findings will aid in designing novel AGT inhibitors that incorporate O(6)-alkylguanine adducts in oligodeoxyribonucleotide contexts.
DOI: 10.1021/bi025857i
PubMed: 12093287
Affiliations:
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Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alkaline Phosphatase (metabolism)</term>
<term>Amino Acid Substitution</term>
<term>Animals</term>
<term>Base Sequence</term>
<term>Crotalus</term>
<term>DNA Repair</term>
<term>Escherichia coli (enzymology)</term>
<term>Kinetics</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mutagenesis, Site-Directed</term>
<term>O(6)-Methylguanine-DNA Methyltransferase (metabolism)</term>
<term>Oligodeoxyribonucleotides (metabolism)</term>
<term>Phosphodiesterase I</term>
<term>Phosphoric Diester Hydrolases</term>
<term>Recombinant Proteins (metabolism)</term>
<term>Substrate Specificity</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Cinétique</term>
<term>Crotalus</term>
<term>Escherichia coli (enzymologie)</term>
<term>Mutagenèse dirigée</term>
<term>O(6)-methylguanine-DNA methyltransferase (métabolisme)</term>
<term>Oligodésoxyribonucléotides (métabolisme)</term>
<term>Phosphatase alcaline (métabolisme)</term>
<term>Phosphodiesterase I</term>
<term>Phosphodiesterases</term>
<term>Protéines recombinantes (métabolisme)</term>
<term>Réparation de l'ADN</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Spécificité du substrat</term>
<term>Substitution d'acide aminé</term>
<term>Séquence nucléotidique</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Alkaline Phosphatase</term>
<term>O(6)-Methylguanine-DNA Methyltransferase</term>
<term>Oligodeoxyribonucleotides</term>
<term>Recombinant Proteins</term>
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<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Escherichia coli</term>
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<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Escherichia coli</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>O(6)-methylguanine-DNA methyltransferase</term>
<term>Oligodésoxyribonucléotides</term>
<term>Phosphatase alcaline</term>
<term>Protéines recombinantes</term>
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<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Animals</term>
<term>Base Sequence</term>
<term>Crotalus</term>
<term>DNA Repair</term>
<term>Kinetics</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mutagenesis, Site-Directed</term>
<term>Phosphodiesterase I</term>
<term>Phosphoric Diester Hydrolases</term>
<term>Substrate Specificity</term>
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<term>Cinétique</term>
<term>Crotalus</term>
<term>Mutagenèse dirigée</term>
<term>Phosphodiesterase I</term>
<term>Phosphodiesterases</term>
<term>Réparation de l'ADN</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Spécificité du substrat</term>
<term>Substitution d'acide aminé</term>
<term>Séquence nucléotidique</term>
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<front><div type="abstract" xml:lang="en">Activity of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) is an important source of tumor cell resistance to alkylating agents. AGT inhibitors may prove useful in enhancing chemotherapy. AGT is inactivated by reacting stoichiometrically with O(6)-benzylguanine (b(6)G), which is currently in clinical trials for this purpose. Short oligodeoxyribonucleotides containing a central b(6)G are more potent inactivators of AGT than b(6)G. We examined whether human AGT could react with oligodeoxyribonucleotides containing multiple b(6)G residues. The single-stranded 7-mer 5'-d[T(b(6)G)(5)G]-3' was an excellent AGT substrate with all five b(6)G adducts repaired although one adduct was repaired much more slowly. The highly b(6)G-resistant Y158H and P140K AGT mutants were also inactivated by 5'-d[T(b(6)G)(5)G]-3'. Studies with 7-mers containing a single b(6)G adduct showed that 5'-d[TGGGG(b(6)G)G]-3' was more poorly repaired by wild-type AGT than 5'-d[T(b(6)G)GGGGG]-3' and 5'-d[TGG(b(6)G)GGG]-3' and was even less repairable by mutants Y158H and P140K. This positional effect was unaffected by interchanging the terminal 5'- or 3'-nucleotides and was also observed with single-stranded 16-mer oligodeoxyribonucleotides containing O(6)-methylguanine, where a minimum of four nucleotides 3' to the lesion was required for the most efficient repair. Annealing with the reverse complementary strands to produce double-stranded substrates increased the ability of AGT to repair adducts at all positions except at positions 2 and 15. Our results suggest that AGT recognizes the polarity of single-stranded DNA, with the best substrates having an adduct adjacent to the 5'-terminal residue. These findings will aid in designing novel AGT inhibitors that incorporate O(6)-alkylguanine adducts in oligodeoxyribonucleotide contexts.</div>
</front>
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<name sortKey="Pauly, Gary T" sort="Pauly, Gary T" uniqKey="Pauly G" first="Gary T" last="Pauly">Gary T. Pauly</name>
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