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Leona D Samson - One of the best experts on this subject based on the ideXlab platform.
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A Chemical and Genetic Approach Together Define the Biological Consequences of 3-Methyladenine Lesions in the Mammalian Genome*
2015Co-Authors: Barry Gold, Leona D SamsonAbstract:DNA-damaging Agents produce a plethora of cellular responses that include p53 induction, cell cycle arrest, and apoptosis. It is generally assumed that it is the DNA damage produced by these Agents that triggers such responses, but there is limited direct evidence to sup-port this assumption. Here, we used DNA alkylation re-pair proficient and deficient isogenic mouse cell lines to demonstrate that the signal to trigger p53 induction, cell cycle arrest, and apoptosis in response to alkylating Agents does emanate from DNA damage. Moreover, we established that 3-methyladenine, a relatively minor DNA lesion produced by most Methylating Agents (which form mainly 7-methylguanine), can specifically induce sister chromatid exchange, chromatid and chro-mosome gaps and breaks, S phase arrest, the accumula
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a chemical and genetic approach together define the biological consequences of 3 methyladenine lesions in the mammalian genome
Journal of Biological Chemistry, 1998Co-Authors: Bevin P Engelward, Andrew J Dreslin, Jack D Kelly, Mavis M Wu, Barry Gold, James M. Allan, Leona D SamsonAbstract:Abstract DNA-damaging Agents produce a plethora of cellular responses that include p53 induction, cell cycle arrest, and apoptosis. It is generally assumed that it is the DNA damage produced by these Agents that triggers such responses, but there is limited direct evidence to support this assumption. Here, we used DNA alkylation repair proficient and deficient isogenic mouse cell lines to demonstrate that the signal to trigger p53 induction, cell cycle arrest, and apoptosis in response to alkylating Agents does emanate from DNA damage. Moreover, we established that 3-methyladenine, a relatively minor DNA lesion produced by most Methylating Agents (which form mainly 7-methylguanine), can specifically induce sister chromatid exchange, chromatid and chromosome gaps and breaks, S phase arrest, the accumulation of p53, and apoptosis. This study was made possible by the generation of 3-methyladenine DNA glycosylase null mutant cells by targeted homologous recombination and by the chemical synthesis of a Methylating agent that almost exclusively produces 3-methyladenine DNA lesions. The combined use of these two experimental tools has defined the biological consequences of 3-methyladenine, a DNA lesion produced by endogenous cellular metabolites, environmental carcinogens, and chemotherapeutic alkylating Agents.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:Abstract In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
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all four known cyclic adducts formed in dna by the vinyl chloride metabolite chloroacetaldehyde are released by a human dna glycosylase
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: M K Dosanjh, Leona D Samson, Ahmed Chenna, Edward Kim, Heinz Fraenkelconrat, Brett C SingerAbstract:Abstract We have previously reported that human cells and tissues contain a 1,N6-ethenoadenine (epsilon A) binding protein, which, through glycosylase activity, releases both 3-methyladenine (m3A) and epsilon A from DNA treated with Methylating Agents or the vinyl chloride metabolite chloroacetaldehyde, respectively. We now find that both the partially purified human epsilon A-binding protein and cell-free extracts containing the cloned human m3A-DNA glycosylase release all four cyclic etheno adducts--namely epsilon A, 3,N4-ethenocytosine (epsilon C), N2,3-ethenoguanine (N2,3-epsilon G), and 1,N2-ethenoguanine (1,N2-epsilon G). Base release was both time and protein concentration dependent. Both epsilon A and epsilon C were excised at similar rates, while 1,N2-epsilon G and N2,3-epsilon G were released much more slowly under identical conditions. The cleavage of glycosyl bonds of several heterocyclic adducts as well as those of simple methylated adducts by the same human glycosylase appears unusual in enzymology. This raises the question of how such a multiple, divergent activity evolved in humans and what may be its primary substrate.
Bevin P Engelward - One of the best experts on this subject based on the ideXlab platform.
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Homologous recombination prevents methylation-induced toxicity in Escherichia coli
2005Co-Authors: Anetta Nowosielska, Bevin P Engelward, Stephen A. Smith, M. G. MarinusAbstract:Methylating Agents such as N-methyl-N0-nitro-N nitrosoguanidine (MNNG) and methyl methane sulfonate (MMS) produce a wide variety of N- and O-methylated bases in DNA, some of which can block replication fork progression. Homologous recombination is a mechanism by which chromosome replication can proceed despite the presence of lesions. The two major recombination pathways, RecBCD and RecFOR, which repair double-strand breaks (DSBs) and single-strand gaps respectively, are needed to protect against toxicity with the RecBCD system being more important. We find that recombination-deficient cell lines, such as recBCD recF, and ruvC recG, are as sensitive to the cytotoxic effects of MMS and MNNG as the most base excision repair (BER)-deficient (alkA tag) isogenic mutant strain. Recombination and BER-deficient double mutants (alkA tag recBCD) were more sensitive to MNNG and MMS than the single mutants suggesting that homologous recombination and BER play essential independent roles. Cells deleted for the polA (DNA polymerase I) or priA (primosome) genes are as sensitive to MMS and MNNG as alkA tag bacteria. Our results suggest that the mechanism of cytotoxicity by alkylating Agents includes the necessity for homologous recombination to repair DSBs and single-strand gaps produced by DNA replication at blocking lesions or single-strand nicks resulting from AP-endonuclease action
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a chemical and genetic approach together define the biological consequences of 3 methyladenine lesions in the mammalian genome
Journal of Biological Chemistry, 1998Co-Authors: Bevin P Engelward, Andrew J Dreslin, Jack D Kelly, Mavis M Wu, Barry Gold, James M. Allan, Leona D SamsonAbstract:Abstract DNA-damaging Agents produce a plethora of cellular responses that include p53 induction, cell cycle arrest, and apoptosis. It is generally assumed that it is the DNA damage produced by these Agents that triggers such responses, but there is limited direct evidence to support this assumption. Here, we used DNA alkylation repair proficient and deficient isogenic mouse cell lines to demonstrate that the signal to trigger p53 induction, cell cycle arrest, and apoptosis in response to alkylating Agents does emanate from DNA damage. Moreover, we established that 3-methyladenine, a relatively minor DNA lesion produced by most Methylating Agents (which form mainly 7-methylguanine), can specifically induce sister chromatid exchange, chromatid and chromosome gaps and breaks, S phase arrest, the accumulation of p53, and apoptosis. This study was made possible by the generation of 3-methyladenine DNA glycosylase null mutant cells by targeted homologous recombination and by the chemical synthesis of a Methylating agent that almost exclusively produces 3-methyladenine DNA lesions. The combined use of these two experimental tools has defined the biological consequences of 3-methyladenine, a DNA lesion produced by endogenous cellular metabolites, environmental carcinogens, and chemotherapeutic alkylating Agents.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:Abstract In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
Pennapa Thongararm - One of the best experts on this subject based on the ideXlab platform.
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modulation of n methyl n nitrosourea mutagenesis in mouse embryo fibroblasts derived from the gpt delta mouse by an inhibitor of the o6 methylguanine methyltransferase mgmt
Chemical Research in Toxicology, 2020Co-Authors: Bogdan I Fedeles, Pennapa Thongararm, Sakunchai Khumsubdee, Amanda Lee Armijo, Apinya Thiantanawat, Jeerawan Promvijit, Panida Navasumrit, Mathuros RuchirawatAbstract:DNA Methylating Agents are abundant in the environment and are sometimes used in cancer chemotherapy. They react with DNA to form methyl-DNA adducts and byproduct lesions that can be both toxic and mutagenic. Foremost among the mutagenic lesions is O6-methylguanine (m6G), which base pairs with thymine during replication to cause GC→AT mutations. The gpt delta C57BL/6J mouse strain of Nohmi et al. (Mol. Mutagen, 1996;28:465–70) reliably produces mutational spectra of many of DNA damaging Agents. In this work, mouse embryo fibroblasts (MEFs) were made from gpt delta C57BL/6J mice and evaluated as a screening tool to determine the qualitative and quantitative features of mutagenesis by N-methyl-N-nitrosourea (MNU), a direct-acting DNA alkylator that serves as a model for environmental N-nitrosamines, such as N-nitrosodimethylamine and therapeutic Agents such as temozolomide. The DNA repair protein MGMT (O6-methylguanine DNA methyltransferase) protects against environmental mutagenesis by DNA Methylating agen...
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modulation of n methyl n nitrosourea mutagenesis in mouse embryo fibroblasts derived from the gpt delta mouse by an inhibitor of the o6 methylguanine methyltransferase mgmt
Chemical Research in Toxicology, 2020Co-Authors: Pennapa Thongararm, Sakunchai Khumsubdee, Amanda Lee Armijo, Ogda I Fedeles, Lina Kim, Apinya Thiantanawa, Jeerawa Promviji, Panida NavasumriAbstract:DNA Methylating Agents are abundant in the environment and are sometimes used in cancer chemotherapy. They react with DNA to form methyl-DNA adducts and byproduct lesions that can be both toxic and...
Andrew J Dreslin - One of the best experts on this subject based on the ideXlab platform.
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a chemical and genetic approach together define the biological consequences of 3 methyladenine lesions in the mammalian genome
Journal of Biological Chemistry, 1998Co-Authors: Bevin P Engelward, Andrew J Dreslin, Jack D Kelly, Mavis M Wu, Barry Gold, James M. Allan, Leona D SamsonAbstract:Abstract DNA-damaging Agents produce a plethora of cellular responses that include p53 induction, cell cycle arrest, and apoptosis. It is generally assumed that it is the DNA damage produced by these Agents that triggers such responses, but there is limited direct evidence to support this assumption. Here, we used DNA alkylation repair proficient and deficient isogenic mouse cell lines to demonstrate that the signal to trigger p53 induction, cell cycle arrest, and apoptosis in response to alkylating Agents does emanate from DNA damage. Moreover, we established that 3-methyladenine, a relatively minor DNA lesion produced by most Methylating Agents (which form mainly 7-methylguanine), can specifically induce sister chromatid exchange, chromatid and chromosome gaps and breaks, S phase arrest, the accumulation of p53, and apoptosis. This study was made possible by the generation of 3-methyladenine DNA glycosylase null mutant cells by targeted homologous recombination and by the chemical synthesis of a Methylating agent that almost exclusively produces 3-methyladenine DNA lesions. The combined use of these two experimental tools has defined the biological consequences of 3-methyladenine, a DNA lesion produced by endogenous cellular metabolites, environmental carcinogens, and chemotherapeutic alkylating Agents.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:Abstract In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
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repair deficient 3 methyladenine dna glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation induced chromosome damage and cell killing
The EMBO Journal, 1996Co-Authors: Bevin P Engelward, Andrew J Dreslin, J Christensen, D Huszar, Carole G Kurahara, Leona D SamsonAbstract:In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating Agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two Methylating Agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating Agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these Agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.
Sakunchai Khumsubdee - One of the best experts on this subject based on the ideXlab platform.
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modulation of n methyl n nitrosourea mutagenesis in mouse embryo fibroblasts derived from the gpt delta mouse by an inhibitor of the o6 methylguanine methyltransferase mgmt
Chemical Research in Toxicology, 2020Co-Authors: Bogdan I Fedeles, Pennapa Thongararm, Sakunchai Khumsubdee, Amanda Lee Armijo, Apinya Thiantanawat, Jeerawan Promvijit, Panida Navasumrit, Mathuros RuchirawatAbstract:DNA Methylating Agents are abundant in the environment and are sometimes used in cancer chemotherapy. They react with DNA to form methyl-DNA adducts and byproduct lesions that can be both toxic and mutagenic. Foremost among the mutagenic lesions is O6-methylguanine (m6G), which base pairs with thymine during replication to cause GC→AT mutations. The gpt delta C57BL/6J mouse strain of Nohmi et al. (Mol. Mutagen, 1996;28:465–70) reliably produces mutational spectra of many of DNA damaging Agents. In this work, mouse embryo fibroblasts (MEFs) were made from gpt delta C57BL/6J mice and evaluated as a screening tool to determine the qualitative and quantitative features of mutagenesis by N-methyl-N-nitrosourea (MNU), a direct-acting DNA alkylator that serves as a model for environmental N-nitrosamines, such as N-nitrosodimethylamine and therapeutic Agents such as temozolomide. The DNA repair protein MGMT (O6-methylguanine DNA methyltransferase) protects against environmental mutagenesis by DNA Methylating agen...
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modulation of n methyl n nitrosourea mutagenesis in mouse embryo fibroblasts derived from the gpt delta mouse by an inhibitor of the o6 methylguanine methyltransferase mgmt
Chemical Research in Toxicology, 2020Co-Authors: Pennapa Thongararm, Sakunchai Khumsubdee, Amanda Lee Armijo, Ogda I Fedeles, Lina Kim, Apinya Thiantanawa, Jeerawa Promviji, Panida NavasumriAbstract:DNA Methylating Agents are abundant in the environment and are sometimes used in cancer chemotherapy. They react with DNA to form methyl-DNA adducts and byproduct lesions that can be both toxic and...