Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents

Hickman, Mark J.; Samson, Leona D.

doi:10.1073/pnas.96.19.10764

Cited by 263 publications

(169 citation statements)

References 73 publications

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“…Reproductive cell death and apoptosis triggered by O 6 MeG lesions require MMR. 14,15 In this process, the heterodimer MutSa, comprised of MSH2 and MSH6, is critically involved because of its binding to O 6 MeG adducts mispaired with thymine. 13,26 It has been proposed that unsuccessful removal of thymine by MutSa leads to a futile DNA repair cycle that either directly or indirectly, via the formation of DNA double-stranded breaks (DSBs), gives rise to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…14 The MMR protein binding has been shown to be required for O 6 MeG-triggered apoptosis. 15 In line with this, cells lacking either MSH2 or MSH6 are highly resistant to O 6 -methylating agents because they tolerate O 6 MeG lesions. 16,17 MSH2 knockout mice are predisposed to cancer, and cell lines derived from them show microsatellite instability and tolerance to methylating agents.…”

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confidence: 89%

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Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Roos¹,

Christmann²,

Fraser

et al. 2007

Cell Death Differ

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Exposure of stem cells to genotoxins may lead to embryonic lethality or teratogenic effects. This can be prevented by efficient DNA repair or by eliminating genetically damaged cells. Using undifferentiated mouse embryonic stem (ES) cells as a pluripotent model system, we compared ES cells with differentiated cells, with regard to apoptosis induction by alkylating agents forming the highly mutagenic and killing DNA adduct O 6 -methylguanine. Upon treatment with N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG), ES cells undergo apoptosis at much higher frequency than differentiated cells, although they express a high level of the repair protein O 6 -methylguanine-DNA methyltransferase (MGMT). Apoptosis induced by MNNG is due to O 6 -methylguanine DNA adducts, since inhibition of MGMT sensitized ES cells. The high sensitivity of ES cells to O 6 -methylating agents is due to high expression of the mismatch repair proteins MSH2 and MSH6 (MutSa), which declines during differentiation. High MutSa expression in ES cells was related to a high hyperphosphorylated retinoblastoma (ppRb) level and E2F1 activity that upregulates MSH2, causing, in turn, stabilization of MSH6. Non-repaired O 6 -methylguanine adducts were shown to cause DNA doublestranded breaks, stabilization of p53 and upregulation of Fas/CD95/Apo-1 at significantly higher level in ES cells than in fibroblasts. The high apoptotic response of ES cells to O 6 -methylguanine adducts may contribute to reduction of the mutational load in the progenitor population.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Roos¹,

Christmann²,

Fraser

et al. 2007

Cell Death Differ

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“…It acts as a powerful trigger of apoptosis (Kaina et al, 1997;Tominaga et al, 1997;Meikrantz et al, 1998). In the cell killing process driven by O 6 MeG mismatch repair (MMR) is essentially involved (Kat et al, 1993;Kaina et al, 1997;Hickman and Samson, 1999;Pepponi et al, 2003). If O 6 MeG is repaired, cells are either resistant to O 6 MeG-triggered apoptosis or die because of harmful N-alkylation lesions such as 3-methyladenine, 3-methylguanine and apurinic sites that have arisen from N-methylpurine hydrolysis (Lindahl, 2000).…”

Section: Introductionmentioning

confidence: 99%

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Roos¹,

et al. 2006

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Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O 6 -methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O 6 -benzylguanine showed that, in gliomas, the apoptotic signal originates from O 6 -methylguanine (O 6 MeG) and that repair of O 6 MeG by MGMT prevents apoptosis. We further demonstrate that O 6 MeGtriggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O 6 MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O 6 MeGinduced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by cH2AX formation. Glioma cells mutated in DNA-PK cs , which is involved in non-homologous endjoining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.

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“…For example, following treatment with 6-TG or high levels of IR hMSH2-or hMLH1-deficient tumor cells displayed a shortened G 2 arrest marked by a defect in cdc2 phosphorylation. [24][25][26] Cisplatin treatment exposed a cell cycle checkpoint at the G 1 /S boundary that also appears to depend on functional hMSH2, hMLH1 and hPMS2. 27 This MMR-dependent G 1 /S checkpoint appears to be p53-independent and is similar to a previously described rapid damage response pathway 28 that results in degradation of cyclin D1 and failure to appropriately phosphorylate (inactivate) the RB tumor suppressor protein required for S-phase entry.…”

Section: Autosomal Dominant Cancer Predisposition Syndromesmentioning

confidence: 99%

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Heinen

Schmütte²,

Fishel³

2002

Cancer Biology & Therapy

108

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The discovery that alterations of the DNA mismatch repair system (MMR) were linked to the common human cancer susceptibility syndrome hereditary nonpolyposis colon cancer (HNPCC) resulted in the declaration of a third class of genes involved in tumor development. In addition to oncogenes and tumor suppressors, alterations of DNA repair genes involved in maintaining genomic stability were found to be a clear cause of tumorigenesis. Nearly all tumors display some form of genomic instability, whether it is on the level of the single nucleotides or chromosomes. This observation suggested that the establishment of genomic instability, termed the Mutator Phenotype, was an important aspect of tumor development.

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Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents

Cited by 263 publications

References 73 publications

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

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