Die Mutationstheorie der Geschwulstentstehung

Bauer, Karl-Heinrich

doi:10.1007/978-3-642-86062-1_12

Cited by 10 publications

(9 citation statements)

References 157 publications

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“…Chemical and physical damage to DNA can cause mutations and ultimately cancer, cardiovascular disease, aging, and other diseases (1)(2)(3)(4). This damage can result from endogenous agents or exogenous chemicals.…”

mentioning

confidence: 99%

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Choi

Chowdhury

Hong

et al. 2006

Journal of Biological Chemistry

125

207

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Chemical and physical damage to DNA can cause mutations and ultimately cancer, cardiovascular disease, aging, and other diseases (1-4). This damage can result from endogenous agents or exogenous chemicals. Many types of damage are known, and the biological effects can vary considerably. One of the prominent types of damage is alkylation at the O-6 atom of guanine (5, 6). O 6 -AlkylG 4 lesions are some of the more mutagenic lesions formed from DNA-alkylating agents (5, 7). The ability of O 6 -alkylG adducts to cause mutations has been demonstrated directly in site-specific mutagenesis experiments with defined adducts (8 -12). Further support for the view that these are deleterious species derives from the existence of specific DNA repair systems for this type of damage in almost all species, ranging from most bacteria to humans (13,14).Different alkylating agents form O 6 -alkylG adducts, and structure-activity relationships are important for understanding the basic mechanisms of how DNA polymerases function as well as issues such as carcinogenesis. Ϫ and HIV-1 RT (16) and by others with several DNA polymerases, mostly bacterial (7,17,18). Some of the more significant conclusions with pol T7Ϫ and HIV-1 RT were that the bulk of the adduct at the O-6 atom had an inhibitory effect and that an inactive polymerase-oligonucleotide complex is in equilibrium with the functional form (16,19).Studies with pol T7 Ϫ and HIV-1 RT indicated that the effect of size at the N-2 atom is more severe than at the O-6 atom (16, * This work was supported in part by United States Public Health Service Grants R01 CA059887, R01 CA115309 (to L. A. P.), R01 ES010375, and P30 ES000267 (to F. P. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains a MALDI-TOF mass spectrum and capillary gel electrophoresis analysis of the O 6 -PobG 36-mer, an electrophoretic gel showing the lack of extension of an O 6 -PobG:G mispair by pol , and mass spectral analyses used to obtain the results shown in Fig. 7 4 The generic term "alkyl" is used to include both alkyl and aralkyl (Bz) groups for convenience. 5 The abbreviations used are: Bz, benzyl; CID, collision-induced dissociation; dCTP␣S, 2Ј-deoxycytidine 5Ј-O-(1-thiotriphosphate); DTT, dithiothreitol; ESI, electrospray ionization; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MALDI-TOF, matrix-assisted laser desorption ionization/time-of-flight; MS, mass spectrometry; Pob, 4-oxo-4-(3-pyridyl)butyl; PCNA, proliferating cell nuclear antigen; pol, (DNA) polymerase; pol T7 Ϫ , bacteriophage pol T7 exonuclease-deficient; RT, reverse transcriptase; UDG, uracil DNA glycosylase; HIV-1, human immunodeficiency virus, type 1.

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mentioning

confidence: 99%

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Choi

Chowdhury

Hong

et al. 2006

Journal of Biological Chemistry

125

207

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“…The somatic theory of cancer holds that carcinogens are mutagens, at least with regard to what are classically termed tumor initiators (1)(2)(3). In a general model, cells are initiated by damage resulting from a DNA-alkylating agent, yielding mutations that are fixed by subsequent rounds of replication.…”

mentioning

confidence: 99%

S-(2-Chloroethyl)glutathione-generated p53 Mutation Spectra Are Influenced by Differential Repair Rates More than Sites of Initial DNA Damage

Valadez

Guengerich

2004

Journal of Biological Chemistry

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Several steps occur between the reaction of a chemical with DNA and a mutation, and each may influence the resulting mutation spectrum, i.e. nucleotides at which the mutations occur. The half-mustard S-(2-bromoethyl)glutathione is the reactive conjugate implicated in ethylene dibromide-induced mutagenesis attributed to the glutathione-dependent pathway. A human p53-driven Ade reporter system in yeast was used to study the factors involved in producing mutations. The synthetic analog S-(2-chloroethyl)glutathione was used to produce DNA damage; the damage to the p53 exons was analyzed using a new fluorescence-based modification of ligation-mediated polymerase chain reaction and an automated sequencer. The mutation spectrum was strongly dominated by the G to A transition mutations seen in other organisms with S-(2-chloroethyl)glutathione or ethylene dibromide. The mutation spectrum clearly differed from the spontaneous spectrum or that derived from N-ethyl,N-nitrosourea. Distinct differences were seen between patterns of modification of p53 DNA exposed to the mutagen in vitro versus in vivo. In the four p53 exons in which mutants were analyzed, the major sites of mutation matched the sites with long half-lives of repair much better than the sites of initial damage. However, not all slowly repaired sites yielded mutations in part because of the lack of effect of mutations on phenotype. We conclude that the rate of DNA repair at individual nucleotides is a major factor in influencing the mutation spectra in this system. The results are consistent with a role of N 7 -guanyl adducts in mutagenesis.The somatic theory of cancer holds that carcinogens are mutagens, at least with regard to what are classically termed tumor initiators (1-3). In a general model, cells are initiated by damage resulting from a DNA-alkylating agent, yielding mutations that are fixed by subsequent rounds of replication. Mutation spectra are generally observed when chemical damage to the DNA occurs; i.e. the sites of the mutation are not random and are often characteristic of the DNA-damaging agent (4, 5). Sometimes mutant spectra can be measured in tumors (in experimental animals or humans), although the existence of any "hotspots" for mutations does not necessarily indicate that the particular mutation is the cause of the tumor. The biochemical basis for where mutations occur (i.e. the mutant spectrum) is generally not well understood. Mutation resulting from chemical damage to DNA is a multistep process, and the observed mutant spectrum may be the result of events occurring during five or possibly more individual processes: (i) reaction of the chemical with DNA, (ii) further non-enzymatic reactions of the DNA adduct (e.g. opening of the imidazole ring in the case of guanyl-N 7 alkyl adducts), (iii) DNA repair (or, more specifically, resistance to repair), (iv) the action of DNA polymerases, and (v) the biological effect of a particular nucleotide/amino acid change in the phenotypic assay used.Ethylene dibromide (1,2-dibromoethane, BrCH 2 CH 2 ...

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“…Firstly, for the last 80 years the prevailing paradigm in cancer origin and pathogenesis was exclusively based upon the "somatic mutation hypothesis" [2,46], which states firstly that any case of cancer is derived from a single somatic cell that has accumulated multiple DNA mutations in genes which control cell proliferation. The mutations are resulted in unprecedentedly intensive reproduction of the transformed cell and in the formation of primary tumor inside the affected tissue.…”

Section: Disposition Of Cancer Around a Bodymentioning

confidence: 99%

“…The Act made big promises, promoted the U.S. National Cancer Institute (NCI) and gave NCI a token measure of independence. The NCI elaborated strategy of the war based on the existed hypothesis of cancerous somatic mutation of an alone cell and subsequent metastasis of its diseased offspring around affected human body to form secondary (metastatic or dispersed) tumors [2].…”

Section: Introductionmentioning

confidence: 99%

Functions of hereditary immunity and xenogamy in cancer origin and pandemic spread

Rumyantsev¹

2011

OJI

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The efficacy of means exploited currently for cancer prevention and treatment appeared to be very low. New insights into the origin of the disease are sorely needed. The present article synthesizes the results from integrative reconsideration of actual data on cancer from the viewpoint of recent developments in pathology, epidemiology, immunology, genetics, and evolution. In contrast to the 80 years old hypothesis of somatic mutative origin of carcinogenesis, the revealed set of evidence showed the origin of cancerous clones is based on inherent constitutional incongruence between the regulators of cell physiology and their targets realized in inherent immunity of cancerous cells to normal regulation of cell replication and tissue growth. The incongruence arises out of both genome mutations which led to interethnic differences in the regulator-receptor structures and intercourse between ethnoses, the regulator-receptor evolution of which has been processed to deal with different ecologic conditions. The current pandemic spread of cancer is brought about growing expansion of interethnic xenogamy favored by growing industrialization, urbanization, globalization, and migration. The proposed hypothesis of genome intrusion in the origin of cancer induces new research ideas and proposals for cancer prevention and therapy.

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Die Mutationstheorie der Geschwulstentstehung

Cited by 10 publications

References 157 publications

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

S-(2-Chloroethyl)glutathione-generated p53 Mutation Spectra Are Influenced by Differential Repair Rates More than Sites of Initial DNA Damage

Functions of hereditary immunity and xenogamy in cancer origin and pandemic spread

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