Mutational specificity of alkylating agents and the influence of DNA repair

Horsfall, Michael; Gordon, Alasdair J.E.; Burns, Philip A.; Zieleńska, Maria; Vliet, G. M. E. Van Der; Glickman, Barry W.

doi:10.1002/em.2850150208

Cited by 164 publications

(91 citation statements)

References 191 publications

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“…The persistence of O 6 -methylguanine adducts, resulting from alkylating agents, may cause DNA polymerase to misread the base pairing because of the altered hydrogen-bonding properties of a base that contains an additional methyl or ethyl group. Thus, O 6 -methylguanine is read as an adenine and mispairs with thymine (Horsfall et al, 1990). Supporting these data, the most common mutations caused by alkylating agents are G : C to A : T transitions (Horsfall et al, 1990), exemplified in the frequent generation of G to A transitions in the oncogene K-ras when the carcinogen N-methylnitrosourea (that forms O 6 -methylguanine adducts) is used in experimentally induced tumor systems (Sukumar et al, 1983;Mitra et al, 1989).…”

Section: Silencing Of Mgmt Causes a New Mutator Pathway In Human Cancermentioning

confidence: 85%

“…Thus, O 6 -methylguanine is read as an adenine and mispairs with thymine (Horsfall et al, 1990). Supporting these data, the most common mutations caused by alkylating agents are G : C to A : T transitions (Horsfall et al, 1990), exemplified in the frequent generation of G to A transitions in the oncogene K-ras when the carcinogen N-methylnitrosourea (that forms O 6 -methylguanine adducts) is used in experimentally induced tumor systems (Sukumar et al, 1983;Mitra et al, 1989). Avoidance of the mutagenic effect is directly related to the presence of a functional MGMT protein (Pegg et al, 1995).…”

Section: Silencing Of Mgmt Causes a New Mutator Pathway In Human Cancermentioning

confidence: 99%

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Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

2004

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O 6 -methylguanine DNA methyltransferase (MGMT) is a key enzyme in the DNA repair network. MGMT removes mutagenic and cytotoxic adducts from O 6 -guanine in DNA, the preferred point of attack of many carcinogens (i.e. methylnitrosourea) and alkylating chemotherapeutic agents (i.e. BCNU, temozolamide, etc.). Hypermethylation of the CpG island located in the promoter region of MGMT is primarily responsible for the loss of MGMT function in many tumor types. The methylation-mediated silencing of MGMT has two consequences for cancer. First, tumors with MGMT methylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in cancer etiology, such as the tumor suppressor p53 and the oncogene K-ras. Second, MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy. These recent results underscore the importance of MGMT in basic and translational cancer research.

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Section: Silencing Of Mgmt Causes a New Mutator Pathway In Human Cancermentioning

confidence: 85%

Section: Silencing Of Mgmt Causes a New Mutator Pathway In Human Cancermentioning

confidence: 99%

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

2004

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“…Alkylnitrosoureas preferentially cause GC4AT transitions at Gs preceded by a Pu residue in E. coli (Jurado et al, 1995;RoldaÁ n-Arjona et al, 1994;Richardson et al, 1987;Burns et al, 1988) and in eukaryotes (Inga et al, 1995;Kunz and Mis, 1989;Minnick et al, 1992;Moriwaki et al, 1991;Palombo et al, 1992). The 5'-¯anking purine eect has been explained as the consequence of a structural in¯uence on the initial formation of O6-alkylguanine, which may be further enhanced by alkylation speci®c repair (Horsfall et al, 1990). It is known that CCNU shows a sequence-dependent reactivity (Erickson et al, 1980;Briscoe et al, 1990;Hartley et al, 1986;Prakash and Gibson, 1992): the middle G in a run of three or more Gs is the most reactive.…”

Section: Discussionmentioning

confidence: 99%

Determining mutational fingerprints at the human p53 locus with a yeast functional assay: a new tool for molecular epidemiology

Inga¹,

Iannone²,

Monti³

et al. 1997

Oncogene

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In order to isolate experimentally induced p53 mutations, a yeast expression vector harbouring a human wild-type p53 cDNA was treated in vitro with the antineoplastic drug chloroethyl-cyclohexyl-nitroso-urea (CCNU) and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. p53 mutations were identi®ed in 32 out of 39 plasmids rescued from independent ade-transformants. Ninety-two percent of CCNU induced mutations were GC-targeted single base pair substitutions, and GC4AT transitions represented 73% of all single base pair substitutions. In 70% of the cases the mutated G was preceded 5' by a purine. The distribution of the mutations along the p53 cDNA was not random: positions 734 and 785 appeared as CCNU mutational hotspots (n=3, P50.0003) and CCNU induced only GC4AT transitions at those positions. The features of these CCNU-induced mutations are consistent with the hypothesis that O6-alkylguanine is the major causative lesion. One third of the CCNUinduced mutants were absent from a huge collection of 4496 p53 mutations in human tumours and cell lines, thus demonstrating that CCNU has a mutational spectrum which is uniquely dierent from that of naturally selected mutations. This strategy allows direct comparison of observed natural mutation spectra with experimentally induced mutation spectra and opens the way to a more rigorous approach in the ®eld of molecular epidemiology.

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“…So, Ada protein is able to decrease the mutagenic lesions induced by MNNG in H 2 O 2 -pretreated cells. Horsfall et al (1990) have shown that the DNA context influences both the distribution and reparability of alkylation damage. This observation may provide information on the cross-adaptive response between H 2 O 2 and MNNG, since the DNA alkylation pattern induced by MNNG can be altered when the DNA has already been oxidized.…”

Section: Cross-adaptive Response Between H 2 O 2 and Mnngmentioning

confidence: 99%

Several pathways of hydrogen peroxide action that damage the E. coli genome

Asad

Almeida

et al. 2004

Genet. Mol. Biol.

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Hydrogen peroxide is an important reactive oxygen species (ROS) that arises either during the aerobic respiration process or as a by-product of water radiolysis after exposure to ionizing radiation. The reaction of hydrogen peroxide with transition metals imposes on cells an oxidative stress condition that can result in damage to cell components such as proteins, lipids and principally to DNA, leading to mutagenesis and cell death. Escherichia coli cells are able to deal with these adverse events via DNA repair mechanisms, which enable them to recover their genome integrity. These include base excision repair (BER), nucleotide excision repair (NER) and recombinational repair. Other important defense mechanisms present in Escherichia coli are OxyR and SosRS anti-oxidant inducible pathways, which are elicited by cells to avoid the introduction of oxidative lesions by hydrogen peroxide. This review summarizes the phenomena of lethal synergism between UV irradiation (254 nm) and H 2 O 2 , the cross-adaptive response between different classes of genotoxic agents and hydrogen peroxide, and the role of copper ions in the lethal response to H 2 O 2 under low-iron conditions. Key words: hydrogen peroxide, cross-adaptive response, lethal synergism, copper and iron. General AspectsThe appearance of aerobic forms of life was an important step in the evolutionary process, since oxygen consumption leads to the production of ten-fold more energy from glucose than does anaerobic metabolism (Meneghini, 1987). However, this process imposes constraints on cell viability, because of the generation of reactive oxygen species during respiration.The consecutive univalent reduction of molecular oxygen to water produces three active intermediates: superoxide anion (O 2 -• ), hydrogen peroxide (H 2 O 2 ) and hydroxyl radical (OH • ). These intermediates, collectively referred to as reactive oxygen species (ROS) are potent oxidants of lipids, proteins, and nucleic acids (Halliwell and Gutteridge, 1984;Mello-Filho and Meneghini, 1985;Meneghini, 1988). Among the oxidative DNA lesions, one of the major classes of DNA damage leads to modification in purine and pyrimidine bases, together with oligonucleotide strand breaks, DNA-protein cross-links and abasic sites. Increasing evidence suggests that the cumulative damage caused by ROS contributes to numerous degenerative diseases associated with aging, such as atherosclerosis, rheumatoid arthritis and cancer (Ames et al., 1993;Halliwell and Gutteridge, 1999).Living organisms have developed specific mechanisms to prevent the production and effects of ROS. The reduction of O 2 by cytochrome oxidase without yielding ROS, the superoxide dismutase catalysis of O 2 -• into H 2 O 2 through a dismutation reaction, the decomposition of H 2 O 2 by catalase and peroxidases, and the scavenging of ROS by some vitamins comprise part of the set of cellular antioxidant defenses (Halliwell and Gutteridge, 1999). Synthesis of the enzymes that catalyze these reactions is a part of the adaptive response tr...

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Mutational specificity of alkylating agents and the influence of DNA repair

Cited by 164 publications

References 191 publications

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

Determining mutational fingerprints at the human p53 locus with a yeast functional assay: a new tool for molecular epidemiology

Several pathways of hydrogen peroxide action that damage the E. coli genome

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