DNA Adducts, Mutations, and Cancer 2000

Hemminki, Kari; Koskinen, Mikko; Rajaniemi, Heli; Zhao, Chunyan

doi:10.1006/rtph.2000.1431

Cited by 87 publications

(54 citation statements)

References 86 publications

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“…Error-prone replication of adducted DNA templates during S-phase can generate mutations. Potentially, mutations that activate oncogenes or inactivate tumor-suppressor genes can contribute to multistep carcinogenesis (2,3). Chromosomal DNA is continuously exposed to genotoxic insults from both endogenous and exogenous sources.…”

Section: Polycyclic Aromatic Hydrocarbons Such As Benzo[a]pyrene (B[a]p)mentioning

confidence: 99%

DNA Polymerase κ Is Specifically Required for Recovery from the Benzo[a]pyrene-Dihydrodiol Epoxide (BPDE)-induced S-phase Checkpoint

Slater

Ohmori

et al. 2005

Journal of Biological Chemistry

133

139

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Previously we identified an intra-S-phase cell cycle checkpoint elicited by the DNA-damaging carcinogen benzo[a]pyrene-dihydrodiol epoxide (BPDE). Here we have investigated the roles of lesion bypass DNA polymerases pol and pol in the BPDE-induced S-phase checkpoint. BPDE treatment induced the re-localization of an ectopically expressed green fluorescent proteinpol fusion protein to nuclear foci containing sites of active DNA synthesis in human lung carcinoma H1299 cells. In contrast, a similarly expressed yellow fluorescent protein-pol fusion protein showed a constitutive nuclear focal distribution at replication forks (in the same cells) that was unchanged in response to BPDE. BPDE-induced formation of green fluorescent proteinpol nuclear foci was temporally coincident with checkpoint-mediated S-phase arrest. Unlike "wild-type" cells, Polk ؊/؊ mouse embryonic fibroblasts (MEFs) failed to recover from BPDE-induced S-phase arrest, while exhibiting normal recovery from S-phase arrest induced by ionizing radiation and hydroxyurea. XPV fibroblasts lacking pol showed a normal S-phase checkpoint response to BPDE (but failed to recover from the UV lightinduced S-phase checkpoint), in sharp contrast to Polk ؊/؊ MEFs. The persistent S-phase arrest in BPDEtreated Polk ؊/؊ cells was associated with increased levels of histone ␥H2AX (a marker of DNA double-strand breaks (DSBs)) and activation of the DSB-responsive kinases ATM and Chk2. These data suggest that in the absence of pol, replication forks stall at sites of damage and collapse and generate DSBs. Therefore, we conclude that the trans-lesion synthesis enzyme pol is specifically required for normal recovery from the BPDE-induced S-phase checkpoint. Chromosomal DNA is continuously exposed to genotoxic insults from both endogenous and exogenous sources. Therefore, cells have evolved various mechanisms to minimize the detrimental effects of DNA damage. Cell cycle checkpoints are signal transduction mechanisms that respond to DNA damage by exerting negative controls over cell cycle progression (4). The cell cycle delays triggered by checkpoints enable integration of DNA repair with cell cycle progression following acquisition of DNA damage. Cell cycle checkpoint pathways can arrest cells at the G 1 /S transition, within S-phase (termed the "S-phase checkpoint" or "intra-S-phase checkpoint"), and at G 2 /M. It is widely hypothesized that cell cycle checkpoints are important tumor-suppressive mechanisms that contribute to the maintenance of genomic stability. Consistent with this hypothesis, individuals with congenital defects in checkpoint genes (e.g. p53, CHK2, and ATM) show increased propensity to tumorigenesis.Many components of cell cycle checkpoint signaling cascades have been identified. It is now clear that partially separable checkpoint pathways respond to different forms of DNA damage. For example, DNA double strand breaks (DSB) activate the proximal ATM kinase that signals through the downstream kinase Chk2 and other effectors (5). In contrast, bulky DNA lesion...

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Section: Polycyclic Aromatic Hydrocarbons Such As Benzo[a]pyrene (B[a]p)mentioning

confidence: 99%

DNA Polymerase κ Is Specifically Required for Recovery from the Benzo[a]pyrene-Dihydrodiol Epoxide (BPDE)-induced S-phase Checkpoint

Slater

Ohmori

et al. 2005

Journal of Biological Chemistry

133

139

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“…A formação e detecção de adutos promovidos por ROS e por produtos da peroxidação lipídica têm sido cada vez mais estudadas 183,184 e sua correlação com a carcinogênese cada vez mais relevante [185][186][187][188] . Deste modo, a formação de adutos entre o DOVA e a dGuo constitui mais um dano ao DNA, entre os promovidos po ALA, poderiam levar à mutagênese 164 .…”

Section: Esquema 2 Estrutura E Formação Dos Adutos Dova-dguo E Seus unclassified

“…128,184 . As ROS e os aldeídos produzidos durante a peroxidação lipídica são considerados agentes importantes na indução de lesões ao DNA 224 que podem levar a mutações que têm sido relacionadas com o desenvolvimento do câncer 128,183,188,225 . A célula possui inúmeros sistemas enzimáticos responsáveis pelo reparo de lesões ocorridas no DNA, inclusive as oxidativas 139,142,226 .…”

Section: Mutagenicidade Do Ala E Do Dovaunclassified

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

Onuki¹,

Teixeira²,

Medeiros³

et al. 2002

Quím. Nova

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Recebido em 26/6/01; aceito em 1/10/01 DNA DAMAGE INDUCED BY 5-AMINOLEVULINIC ACID: A POSSIBLE ASSOCIATION WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN ACUTE INTERMITTENT PORPHYRIA PATIENTS. 5-Aminolevulinic acid (ALA) is a heme precursor accumulated in acute intermittent porphyria (AIP), which might be associated with hepatocellular carcinoma (HCC) in symptomatic patients. Under metal catalyzed oxidation, ALA and its cyclic dimerization product, 3,6-dihydropyrazine-2,5-dipropanoic acid, produce reactive oxygen species that damage plasmid and calf thymus DNA bases, increase the steady state level of 8-oxo-7,8-dihydro-2´-deoxyguanosine in liver DNA and promote mitochondrial DNA damage. The final product of ALA, 4,5-dioxovaleric acid (DOVA), is able to alkylate guanine moieties, producing adducts. ALA and DOVA are mutagenic in bacteria. This review shows an up-to-date literature data that reinforce the hypothesis that the DNA damage induced by ALA may be associated with the development of HCC in AIP patients.Keywords: 5-aminolevulinic acid; acute intermitent porphyria; DNA damage. PORFIRIASAs porfirias são definidas como doenças inatas ou adquiridas, relacionadas à deficiência de enzimas -inibição ou insuficiência -da via biossintética do grupo heme (Esquema 1) 1 . Esta deficiência resulta na produção excessiva e excreção de porfirinas e de seus precursores 2-6 . As porfirias são tradicionalmente classificadas com base no principal órgão que produz os metabólitos porfíricos em excesso (fígado ou os tecidos eritropoiéticos), na ocorrência ou não de ataques agudos e nas lesões cutâneas (fotossensibilidade) e/ou neurológicas produzidas 5,7,8 . Tipo de porfiria Aguda Hepática CutâneaPorfiria deficiente em ALA desidratase X X Porfiria aguda intermitente (AIP) X X Coproporfiria hereditária (HCP) X X X Porfiria variegata (VP) X X X Porfiria cutânea tarda (PCT) X X Porfiria eritropoiética congênita (CEP) X Protoporfiria eritropoiética (EPP) X A natureza molecular do defeito genético é altamente heterogê-nea e defeitos múltiplos têm sido demonstrados em cada tipo de porfiria 3,5 . Alguns modelos animais para os estudos dos diferentes tipos de porfiria já existem naturalmente, no caso de EPP e CEP e alguns foram desenvolvidos em laboratório, para EPP e porfirias hepáticas 9,10

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“…NA is a target for many xenobiotica and endogenous compounds. Electrophiles from either source can interact covalently with DNA with the formation of so called DNA adducts [1]. These adducts are believed to be the cause for an increased risk of cancer.…”

mentioning

confidence: 99%

Structural characterization of melphalan modified 2′-oligodeoxynucleotides by miniaturized LC-ES MS/MS

Driessche

Lemière

Dongen

et al. 2004

J. Am. Soc. Mass Spectrom.

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In this study a miniaturized LC coupled to electrospray tandem mass spectrometry was used to analyze modifications originating from the interaction between the chemotherapeutic agent melphalan and 2Ј-oligodeoxynucleotides. Low energy CAD product ion spectra gave information about the specificity of melphalan alkylation with regard to certain DNA sequences. These data can be very useful to estimate the risk in the development of secondary leukaemia as a result of a melphalan cure. In the study of the interaction between melphalan and d(GG), differentiation could be made between alkylation on the 5Ј-side and alkylation on the 3Ј-side, because of the presence or absence of the alkylated w 1 fragment in the low energy CAD spectra. In the other di-mers alkylation specificity for the different bases could be observed. Melphalan alkylation occurs in the sequence G Ͼ A Ͼ C Ͼ T. The study of the alkylated d(GGGG) revealed the presence of mainly 5Ј-end alkylation. Furthermore studies were performed which investigated other melphalan treated di-, tetra-, hepta-, and octa-mers. NA is a target for many xenobiotica and endogenous compounds. Electrophiles from either source can interact covalently with DNA with the formation of so called DNA adducts [1]. These adducts are believed to be the cause for an increased risk of cancer. One of these alkylating agents is the nitrogen mustard melphalan currently used as a chemotherapeutic agent in the treatment of malignant melanoma, multiple myeloma, lymphomas and ovarian carcinoma [2]. DNA adduct formation in perfectly healthy cells at the stage of primary cancer treatment might explain the development of a secondary leukaemia afterwards. It is a well known fact throughout literature that melphalan mainly alkylates the N-7 position in a guanine residue [3]. To the best of our knowledge, no information is available on the regioselectivity of melphalan alkylation in 2Ј-oligodeoxynucleotides and/or whole DNA strands. Therefore there were some important issues left as there are the degree of alkylation of G in relation to its position in the sequence, the influence of the neighbors on the degree of alkylation and the fragmentation patterns observed in melphalan modified 2Ј-oligodeoxynucleotides. Furthermore can we detect C, A and/or T adducts and what is the relation with earlier performed experiments on individual 2Ј-deoxynucleotides and -nucleosides [4,5].Electrospray mass spectrometry has become a viable technique for determining both the sequence specificity and the chemical structure of DNA modifications. By using this technology a lot of information was gathered on the adduct formation between potential carcinogens and individual 2Ј-deoxynucleotides (dNMPs) and -nucleosides (dNs). Furthermore modifications in whole DNA strands are studied after enzymatic digestion also resulting in the study of modified dNMPs and dNs [6]. However, this enzymatic digestion eliminates information related to the location of the adduct in the DNA sequence. In this paper we wish to describe a study of th...

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DNA Adducts, Mutations, and Cancer 2000

Cited by 87 publications

References 86 publications

DNA Polymerase κ Is Specifically Required for Recovery from the Benzo[a]pyrene-Dihydrodiol Epoxide (BPDE)-induced S-phase Checkpoint

DNA Polymerase κ Is Specifically Required for Recovery from the Benzo[a]pyrene-Dihydrodiol Epoxide (BPDE)-induced S-phase Checkpoint

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

Structural characterization of melphalan modified 2′-oligodeoxynucleotides by miniaturized LC-ES MS/MS

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