Loss of ATM sensitizes against O6-methylguanine triggered apoptosis, SCEs and chromosomal aberrations

Dębiak, Małgorzata; Nikolova, Teodora; Kaina, Bernd

doi:10.1016/j.dnarep.2003.11.013

Cited by 35 publications

(36 citation statements)

References 57 publications

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“…The apoptotic response may occur by stabilization of p53 via the ATM/ATR-Chk1 pathway (O'Connell and Cimprich, 2005). Interestingly, however, cells deficient in ATM are hypersensitive to methylating agents (Debiak et al, 2004). Similarly, cells lacking XRCC2 are hypersensitive to TMZ and MNNG (Tsaryk et al, 2005).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

Roos¹,

et al. 2006

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“…Replication fork collapse is also likely to occur if significant concentrations of O 6 meG remain unrepaired before DNA replication. Indeed, replication fork collapse resulting in DSBs has been attributed to increased sister-chromatid exchanges in surviving cells after exposure to low concentrations of alkylating agent [61].…”

Section: Discussionmentioning

confidence: 99%

Rapid induction of chromatin-associated DNA mismatch repair proteins after MNNG treatment

Schroering

Williams

2008

DNA Repair

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Treatment with low concentrations of monofunctional alkylating agents induces a G 2 arrest only after the second round of DNA synthesis in mammalian cells and requires a proficient mismatch repair (MMR) pathway. Here we have investigated rapid alkylation-induced recruitment of DNA repair proteins to chromosomal DNA within synchronized populations of MMR proficient cells (HeLa MR) after MNNG treatment. Within the first hour, the concentrations of MutSα and PCNA increase well beyond their constitutive chromosomally bound levels and MutLα is newly recruited to the chromatin-bound MutSα. Remarkably, immunoprecipitation experiments demonstrate rapid association of these proteins on the alkylation-damaged chromatin, even when DNA replication is completely blocked. The extent of association of PCNA and MMR proteins on the chromatin is dependent upon the concentration of MNNG and on the specific type of replication block. A subpopulation of the MutSα-associated PCNA also becomes monoubiquitinated, a known requirement for PCNA to interact with translesion synthesis (TLS) polymerases. In addition, chromatin-bound SMC1 and NBS1 proteins, associated with DNA double-strand-breaks (DSBs), become phosphorylated within one to two hours of exposure to MNNG. However, these activated proteins are not colocalized on the chromatin with MutSα in response to MNNG exposure. PCNA, MutSα/MutLα and activated SMC1/NBS1 remain chromatin-bound for at least 6-8 hours after alkylation damage. Thus, cells that are exposed to low levels of alkylation treatment undergo rapid recruitment to and/or activation of key proteins already on the chromatin without the requirement for DNA replication, apparently via different DNA-damage signaling pathways.

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“…42 ATM, a protein kinase involved in double strand break repair, appears to have a protective function, as ATM2/2 cells are hypersensitive to MNNG. 43 ATM also directly binds hMLH1 and both proteins are present in the BASC complex (see later).…”

Section: Regulation Of Mmrmentioning

confidence: 99%

Structure and function of the components of the human DNA mismatch repair system

Jascur

Boland

2006

Intl Journal of Cancer

101

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DNA mismatch repair (MMR) is one of the several enzyme systems involved in DNA homeostasis. DNA MMR is involved in the repair of specific types of errors that occur during new DNA synthesis; loss of this system leads to an accelerated accumulation of potential mutations, and predisposes to certain types of cancers. Germline mutations in some of the DNA MMR genes cause the hereditary cancer predisposition, Lynch syndrome. This review addresses advances in the biochemistry of DNA MMR and its relationship to carcinogenesis. ' 2006 Wiley-Liss, Inc.Key words: DNA mismatch repair; microsatellite instability; lynch syndrome; HNPCC; colorectal cancer; hMSH2; hMLH1; hMSH6; hPMS2; exonuclease IThe DNA mismatch repair (MMR) system was at one time in the exclusive domain of the microbial biochemist, but has been thrust into the mainstream of the cancer biologist because of its importance in carcinogenesis. Approximately 15% of colorectal cancers develop through mechanisms whereby this form of DNA maintenance is lost, leading to 100-to 1,000-fold increases in error rates during replication. This review of recent progress in DNA MMR research is intended for the tumor biologist who is interested in structural and functional details of this system. There have been several reviews of the clinical aspects of DNA MMR that emphasize the diagnostic uses of testing for microsatellite instability and the use of immunohistochemistry of the DNA MMR proteins in colorectal cancer. [1][2][3][4][5][6][7] This review will serve to complement those reviews, and will highlight some of the biochemical issues that underlie DNA MMR. Components of the DNA MMR systemThe DNA MMR system corrects DNA base pairing errors in newly replicated DNA. The primary DNA polymerase in eukaryotic S phase DNA replication, polymerase d, has 3 0 > 5 0 proofreading activity that corrects 99% of replication errors. Nevertheless, mispaired nucleotides are occasionally left behind, as are small insertion/deletion mutations that are prone to occur at repetitive sequences. Microsatellites are multiple tandem repeats in which the repetitive element consists of a short number of nucleotides (perhaps 6 or fewer, and for functional studies, usually 1-4), and these are particularly prone to slippage and inefficient proofreading by DNA polymerase. The MMR system is critical to correct these problems, and if inactivated, the resulting shortening of microsatellites is a telltale sign of the ensuing ''microsatellite instability'' (MSI) phenotype. MSI testing is most often performed on mononucleotide or dinucleotide repeats.A casual description of the MMR system would state that the MMR system is chiefly a sensory system that scans DNA, and when a nucleotide mispair is detected, removes the error and summons DNA polymerase to repeat the synthesis, and this time corrects the error. This works because even in repetitive sequences, the error rate of DNA polymerase is low, and so simply having a second chance usually fixes the problem.More formally, the MMR system is an excision/resynt...

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Loss of ATM sensitizes against O6-methylguanine triggered apoptosis, SCEs and chromosomal aberrations

Cited by 35 publications

References 57 publications

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

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

Rapid induction of chromatin-associated DNA mismatch repair proteins after MNNG treatment

Structure and function of the components of the human DNA mismatch repair system

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