p53 Interacts with the DNA Mismatch Repair System to Modulate the Cytotoxicity and Mutagenicity of Hydrogen Peroxide

Lin, Xi Zhang; Ramamurthi, Krishna; Mishima, Masanori; Kondo, Akira; Howell, Stephen B.

doi:10.1124/mol.58.6.1222

Cited by 39 publications

(27 citation statements)

References 40 publications

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“…In agreement with the latter possibility, a role of p53 in creating a threshold for recombination between short versus long homologies was proposed from studies on the stability of repetitive sequences (Gebow et al, 2000). In support of a complementary role of p53 and MSH2 in the fidelity control of DNA repair and/or replication, it was found that loss of p53 and MSH2 causes a synergistic increase in the rate of frameshift mutations in CA repair tracts after genotoxic treatment (Lin et al, 2000).…”

Section: Possible Roles Of Focal P53 and Msh2 Enrichments In S Phase mentioning

confidence: 53%

Association of p53 and MSH2 with recombinative repair complexes during S phase

et al. 2002

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Our previous recombination and biochemical analyses have led to the hypothesis that the tumor suppressor p53 monitors homologous recombination, a function which was previously attributed to the mismatch repair protein MSH2. Here, we show that a certain fraction of p53 is concentrated within discrete nuclear foci of cells synchronized in G1 phase, a pattern which becomes even more pronounced in S phase, especially after g-ray treatment. p53 foci show some colocalization with MSH2 within distinct foci during G1 phase, while dots formed by BRCA1 display an independent localization pattern. In S phase nuclei, p53 foci almost completely colocalize with MSH2 foci and associate with the recombination surveillance factor BRCA1 in irradiated S phase cells. These p53 and MSH2 foci also show significant overlaps with foci of the recombination enzymes Rad50 and Rad51, which for the first time unveiled recombination-related functions of p53 in replicating cells. During S phase, p53 and MSH2 are maximally active in binding to early recombination intermediates, and coexist within the same nuclear DNA-protein complexes. Our data suggest that p53 is linked similarly to homologous recombination as MSH2 and provide further evidence for the new concept of a dual role of p53 in the regulation of growth and repair.

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Section: Possible Roles Of Focal P53 and Msh2 Enrichments In S Phase mentioning

confidence: 53%

Association of p53 and MSH2 with recombinative repair complexes during S phase

et al. 2002

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“…It is noteworthy that increased tolerance to DNA adducts is not only seen in MMR deficiency but can also occur following p53 malfunction (see below). Indeed, p53 dysfunction exacerbates cisplatin resistance in MMR-deficient tumor cells (Lin et al, 2000(Lin et al, , 2001, and this is consistent with both a downregulation of hMSH2 by mutant p53 protein and an enhanced replicative bypass (Scherer et al, 1996). Moreover, loss of the p53 function accompanies MMR deficiency in cell lines selected for cisplatin resistance .…”

Section: Increase In Dna Damage Repairmentioning

confidence: 51%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatinbased chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologicbased mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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“…For example, it has been reported that the oxidized nucleoside triphosphate pool is a significant contributor to genomic instability in mismatched repair-deficient cells (25,26). However, this situation is unlikely for MCF-7 cells because there are reports of mismatch repair proficiency for these cells (27)(28)(29).…”

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confidence: 92%

Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry

Hah

Mundt

Kim

et al. 2007

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

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Growing evidence suggests that oxidative damage to cells generates mutagenic 7,8-dihydro-8-oxo-2 -deoxyguanosine (8-oxodG), which may initiate diseases related to aging and carcinogenesis. Kinetic measurement of 8-oxodG metabolism and repair in cells has been hampered by poor assay sensitivity and by difficulty characterizing the flux of oxidized nucleotides through the relevant metabolic pathways. We report here the development of a sensitive and quantitative approach to characterizing the kinetics and metabolic sources of 8-oxodG in MCF-7 human breast cancer cells by accelerator mass spectrometry. We observed that [ 14 C]8-oxodG at medium concentrations of up to 2 pmol/ml was taken up by MCF-7 cells, phosphorylated to mono-, di-, and triphosphate derivatives, and incorporated into DNA. Oxidative stress caused by exposure of the cells to 17␤-estradiol resulted in a reduction in the rate of [ 14 C]8-oxodG incorporation into DNA and an increase in the ratio of 8-oxodG monophosphate (8-oxodGMP) to 8-oxodG triphosphate (8-oxodGTP) in the nucleotide pool. 17␤-Estradiolinduced oxidative stress up-regulated the nucleotide pool cleansing enzyme MTH1 and possibly other Nudix-related pyrophosphohydrolases. These data support the conclusion that 8-oxodGTP is formed in the nucleotide pool by both 8-oxodG metabolism and endogenous reactive oxygen species. The metabolism of 8-oxodG to 8-oxodGTP, followed by incorporation into DNA is a mechanism by which the cellular presence of this oxidized nucleoside can lead to mutations.DNA repair ͉ nucleoside metabolism ͉ oxidative stress ͉ breast cancer

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p53 Interacts with the DNA Mismatch Repair System to Modulate the Cytotoxicity and Mutagenicity of Hydrogen Peroxide

Cited by 39 publications

References 40 publications

Association of p53 and MSH2 with recombinative repair complexes during S phase

Association of p53 and MSH2 with recombinative repair complexes during S phase

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry

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