Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct.

Duckett, Derek R.; Drummond, James T.; Murchie, Alastair I. H.; Reardon, Joyce T.; Sancar, Aziz; Lilley, David M. J.; Modrich, Paul

doi:10.1073/pnas.93.13.6443

Cited by 382 publications

(312 citation statements)

References 42 publications

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“…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. 24,27 If this does not occur, cells will survive and O 6 MeG adducts will give rise to mutations.…”

Section: Discussionmentioning

confidence: 99%

“…10 When O 6 MeG is not repaired by MGMT, it will mispair with thymine during DNA replication 11 and, therefore, in the absence of mismatch repair (MMR), and a second round of replication, indues GC to AT point mutations. 12 In MMR competent cells, the O 6 MeG/thymine mismatch is bound by MutSa, 13 a heterodimer comprised of the proteins MSH2 and MSH6. 14 The MMR protein binding has been shown to be required for O 6 MeG-triggered apoptosis.…”

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confidence: 99%

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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: 99%

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

View full text Add to dashboard Cite

show abstract

“…At least in the case of epirubicin, doxorubicin and mitoxantrone, intercalation may introduce steric alterations in the DNA and/or other damages such as crosslinks or heteroduplexes that are detected by MSH2, like the damages introduced by cisplatin and alkylating agents. 28,29 However, this does not apply to the nonintercalator etoposide. The finding that loss of DNA mismatch repair results in resistance to etoposide, 15 indicates that this mechanism of resistance to topoisomerase II poisons may not be restricted to DNA intercalators.…”

Section: Discussionmentioning

confidence: 99%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repairdeficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poisonmediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.

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“…During replication, O 6 -meG templates incorporation of C or more commonly, T. These might serve as targets for MMR. In vitro studies reveal O 6 -meG mispairs are recognized by MutSα and activate its ATPase activity (Berardini et al, 2000;Duckett et al, 1996).…”

Section: Mmr and Dna Damage Signallingmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct.

Cited by 382 publications

References 42 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

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

DNA mismatch repair: Molecular mechanism, cancer, and ageing

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