A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells

Galloway, Sheila M.; Greenwood, Susan K.; Hill, Rosina; Bradt, Carole I.; Bean, Christian L.

doi:10.1016/0165-7992(95)90040-3

Cited by 66 publications

(27 citation statements)

References 19 publications

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“…We have recently shown that the O 6 -meG DNA adduct is the predominant carcinogenic lesion in MMR competent mice, and based on our data here, suggest that this is also the case for MMR de®cient mice (Allay et al, 1999). Of interest, MMR-defective cells have been shown to have reduced numbers of chromosomal aberrations following methylating agent exposure, indicating that MMR processing of O 6 -meG may be critical to these aberrations (Galloway et al, 1995). From this, we predict that most of the carcinogenic lesions in PMS2 7/7 mice are point mutations rather than chromosomal in nature.…”

supporting

confidence: 69%

“…This futile cycle is associated with DNA double strand breaks whenever the single strand extends to the replication site, either leading to S phase arrest and, ultimately, induction of apoptosis (Meikrantz et al, 1998) and cell death. Surviving cells are loaden with G to A mutations or can undergo nonhomologous recombination and chromosomal rearrangements at the site of the patches (Galloway et al, 1995), contributing to the carcinogenesis of methylating agents in MMR competent animals. In contrast, MMR de®cient cells, due to the lack of initiation of MMR, are tolerance to methylating agents (Fink et al, 1998;Liu et al, 1996) and a large number of O 6 -meG DNA adducts, which we have previously reported to be 96 pg/mg guanine bases 3 h after MNU treatment and over 70 pg/mg guanine bases by 18 h (Liu et al, 1994), are converted to G to A mutations and results in a marked increase in tumorigenesis.…”

mentioning

confidence: 99%

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Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

1999

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supporting

confidence: 69%

mentioning

confidence: 99%

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

1999

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“…That events of this type indeed arise in cells treated with methylating agents was suggested by an increase in SCE frequency in the treated MMR-proficient 293T L␣ + cells (data not shown; N. Mojas, L.Stojic, and J. Jiricny, in prep. ; see also Galloway et al 1995;Kaina et al 1997). The timing of these events broadly coincided with the formation of foci containing RPA, ATR (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

Stojic¹,

Mojas²,

Ćejka³

et al. 2004

Genes Dev.

212

256

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S N 1-type alkylating agents represent an important class of chemotherapeutics, but the molecular mechanisms underlying their cytotoxicity are unknown. Thus, although these substances modify predominantly purine nitrogen atoms, their toxicity appears to result from the processing of O 6 -methylguanine ( 6Me G)-containing mispairs by the mismatch repair (MMR) system, because cells with defective MMR are highly resistant to killing by these agents. In an attempt to understand the role of the MMR system in the molecular transactions underlying the toxicity of alkylating agents, we studied the response of human MMR-proficient and MMR-deficient cells to low concentrations of the prototypic methylating agent N-methyl-N -nitro-N-nitrosoguanidine (MNNG). We now show that MNNG treatment induced a cell cycle arrest that was absolutely dependent on functional MMR. Unusually, the cells arrested only in the second G 2 phase after treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or the inhibition of CHK1, attenuated the arrest. The checkpoint activation was accompanied by the formation of nuclear foci containing the signaling and repair proteins ATR, the S*/T*Q substrate, ␥-H2AX, and replication protein A (RPA). The persistence of these foci implied that they may represent sites of irreparable damage.

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“…The current model, supported by a broad range of evidence, suggests that O 6 MeG pairs with thymine, forming a mismatch that is subject to mismatch repair (MMR) (Karran and Stephenson, 1990;Kat et al, 1993;Duckett et al, 1996). Owing to repetitive, faulty MMR cycles provoked by the mispairing properties of O 6 MeG, secondary DNA lesions are formed, which either directly or upon interference with DNA replication trigger chromosomal damage and cell death, which is executed mainly by apoptosis (Galloway et al, 1995;Kaina et al, 1997;Hickman and Samson, 1999). Cells defective in MMR are highly resistant to O 6 MeG-generating agents such as the model alkylating drug N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) and similar acting anticancer drugs (Kat et al, 1993;Dosch et al, 1998;Marra et al, 2001).…”

Section: Introductionmentioning

confidence: 95%

Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1

2004

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Various tumor-therapeutic drugs and environmental carcinogens alkylate DNA inducing O 6 -methylguanine (O 6 MeG) that provokes cell death by apoptosis. In rodent fibroblasts, apoptosis triggered by O 6 MeG is executed via the mitochondrial damage pathway. Conversion of O 6 MeG into critical downstream lesions requires mismatch repair (MMR). This is thought to signal apoptosis upon binding to O 6 MeG lesions mispaired with thymine. Alternatively, O 6 MeG lesions might be processed by MMR giving rise to DNA double-strand breaks (DSBs) during replication that finally provoke apoptosis. To test this, we examined apoptosis triggered by O 6 MeG in human peripheral lymphocytes in which O 6 -methylguanine-DNA methyltransferase (MGMT) had been inactivated by O 6 -benzylguanine (O 6 BG) and which were not proliferating or proliferating upon CD3/CD28 stimulation. Treatment with N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) or the anticancer drug temozolomide induced apoptosis only in proliferating, but not resting cells. With exceptional high alkylation doses (X15 lM of MNNG), apoptosis was also observed in resting lymphocytes, albeit at a lower level than in proliferating cells. This response was not affected by O 6 BG, suggesting that replication-independent apoptosis at high dose levels is caused by lesions other than O 6 MeG. O 6 MeG-triggered apoptosis in proliferating lymphocytes was preceded by a wave of DSBs, which coincided with p53 and Fas receptor upregulation, while Fas ligand, Bax and Bcl-2 expression was not altered. Treatment with anti-Fas neutralizing antibody attenuated MNNG-induced apoptosis in MGMT-depleted proliferating lymphocytes. The data suggest that O 6 MeG is converted by MMR and DNA replication into DSBs that trigger apoptosis by p53 stabilization and Fas/CD95/Apo-1 upregulation. This is supported by the finding that ionizing radiation, inducing DSBs on its own, provokes apoptosis in lymphocytes in a replication-independent way. The strict proliferation dependence of apoptosis triggered by O 6 MeG may explain the specific killing response of MGMT-deficient proliferating cells, including tumors, to O 6 MeG generating anticancer drugs and suggests that tumor proliferation rate, Fas responsiveness, MGMT and MMR status are important prognosis parameters.

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A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells

Cited by 66 publications

References 19 publications

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1

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A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells

Cited by 66 publications

References 19 publications

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase

Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1

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Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase