The properties of in templates for RNA polymerase

Gerchman, Lois L.; Ludlum, David B.

doi:10.1016/0005-2787(73)90160-3

Cited by 249 publications

(76 citation statements)

References 8 publications

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“…The other, more critical products iriclude phosphotriesters, 3-alkylguanine, 0 ( 4 )· alkylthymine, 7-alkyladenine, and 0(6)-alkylguanine. This last product has been shown to be responsible for mispairing [73,155], and a nurober of investigations with N -nitro so compounds have revealed that argans which readily develop tumors are much less active in the removal of 0(6)-alkylguanine from their DNA than non-targetargans [122,138,192,200,201 ,203].…”

Section: Pattern Of Dna-binding Sitesmentioning

confidence: 99%

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Lutz

1979

Mutation Research/Reviews in Genetic Toxicology

398

124

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Section: Pattern Of Dna-binding Sitesmentioning

confidence: 99%

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Lutz

1979

Mutation Research/Reviews in Genetic Toxicology

398

124

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“…Although constituting only 6% of the total products, O 6 -methylguanine (O 6 -meG) is responsible for the majority of the toxic effects of TMZ (Middleton and Margison, 2003). O 6 -meG is a promutagenic, recombinogenic and cytotoxic DNA lesion (Gerchman and Ludlum, 1973;Brennand and Margison, 1986). These biological effects require two rounds of DNA replication (Kaina et al, 1997) and a functional mismatch repair (MMR) system is obligatory for cell killing (Karran and Bignami, 1994).…”

mentioning

confidence: 99%

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

et al. 2009

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We evaluated the pharmacodynamic effects of the O 6 -methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O 6 -methylguanine (O 6 -meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O 6 -meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O 6 -meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O 6 -meG in PBMC DNA during treatment.

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“…MNU is a strong mutagen and carcinogen while MMS acid has weak activity. This association made by Loveless (18) and supported by the demonstration of Gerchman and Ludlum (26) that there is aberrant base pairing with a polymer containing 06-methylguanine suggests that the mechanism of carcinogenesis by MNU is through a mutation by improper base pairing during DNA replication. If this is the case, then endonuclease II is the first defined enzyme to recognize a potentially carcinogenic base in DNA.…”

Section: Discussionmentioning

confidence: 93%

The Enzymatic Release of O ⁶ -methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N -methyl- N -nitrosourea

Kirtikar

Goldthwait

1974

Proc. Natl. Acad. Sci. U.S.A.

124

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Endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) of Escherichia coli has been shown to break phosphodiester bonds in alkylated DNA and depurinated DNA. The hypothesis that depurination. is a step in the mechanism of the reaction with alkylated DNA is supported by in vitro experiments with DNA reacted with N-methyl-Nl-nitrosourea. Endonuclease I1 releases 08-methylguanine and 3-methyladenine, but not 7-methylguanine, from DNA that has been methylated by the carcinogen N-methyl-N-nitrosourea.Endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) of Escherichia coli is an enzyme capable of breaking p)hosphodiester bonds in DNA which has been reacted with the alkylating agent methyl methanesulfonate (MAIS) (1-3). MMTIS-treated DNA contain.s 7-methylguanine and 3-methyladenine. Endonuclease IT also recognizes dep)urinated and depurinated-reduced sites in DNA (4) and at high concentrations makes a limited iiumber of single-strand breaks in native DNA from T-4 and T-7 bacterioplhages (5). The enzyme hydrolyses the phosphodiester bond.s in native D)NA to yield 5'-phosphomonoesters (5), and indirect evidence has been presented to support the proposal that enzymeinduced chain breaks are on the 5'-phosphate side of the depurinated reduced sites (5). Because the enzyme recognizes both alkylated and depurinated sites in the DNA, it was l)ostillated that the process of depurination was an intermediate step prior to phosphodiester bond cleavage of alkylated DNA. Enzymatic depurination by the endonuclease II preparation has now been demonstrated. This has allowed us to observe a specificity of the enzyme for some but not all of the methylated bases. This paper describes the ability of the enzyme to release 00-methylguanine and 3-methyladenine, and the inability of the enzyvme to release 7-methylguanine from DNA 'that has been methylated by the carcinogen ,Nmethyl-N-nitrosourea (MNU).

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The properties of in templates for RNA polymerase

Cited by 249 publications

References 8 publications

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

The Enzymatic Release of O ⁶ -methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N -methyl- N -nitrosourea

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The properties of in templates for RNA polymerase

Cited by 249 publications

References 8 publications

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

The Enzymatic Release of O 6 -methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N -methyl- N -nitrosourea

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The Enzymatic Release of O ⁶ -methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N -methyl- N -nitrosourea