Base excision repair and nucleotide excision repair contribute to the removal of N-methylpurines from active genes

Plosky, Brian S.; Samson, Leona D.; Engelward, Bevin P.; Gold, Barry; Schlaen, B. R.; Millas, Themistocles; Magnotti, Michael; Schor, J. A.; Scicchitano, David A.

doi:10.1016/s1568-7864(02)00075-7

Cited by 67 publications

(44 citation statements)

References 51 publications

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“…In the absence of Aag, compensatory pathways (alternative DNA glycosylases or the nucleotide excision repair pathway) (27,34) did not effectively remove MMS-induced or MNNGinduced alkylation damage. Accumulated alkylation damage then slows progression of the replication fork in a checkpointindependent fashion (40).…”

Section: Discussionmentioning

confidence: 93%

Base Excision Repair Intermediates Induce p53-independent Cytotoxic and Genotoxic Responses

Sobol

Kartalou

Almeida

et al. 2003

Journal of Biological Chemistry

171

158

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DNA alkylation damage is primarily repaired by the base excision repair (BER) machinery in mammalian cells. In repair of the N-alkylated purine base lesion, for example, alkyl adenine DNA glycosylase (Aag) recognizes and removes the base, and DNA polymerase ␤ (␤-pol) contributes the gap tailoring and DNA synthesis steps. It is the loss of ␤-pol-mediated 5 -deoxyribose phosphate removal that renders mouse fibroblasts alkylation-hypersensitive. Here we report that the hypersensitivity of ␤-pol-deficient cells after methyl methanesulfonate-induced alkylation damage is wholly dependent upon glycosylase-mediated initiation of repair, indicating that alkylated base lesions themselves are tolerated in these cells and demonstrate that ␤-pol protects against accumulation of toxic BER intermediates. Further, we find that these intermediates are initially tolerated in vivo by a second repair pathway, homologous recombination, inducing an increase in sister chromatid exchange events. If left unresolved, these BER intermediates trigger a rapid block in DNA synthesis and cytotoxicity. Surprisingly, both the cytotoxic and genotoxic signals are independent of both the p53 response and mismatch DNA repair pathways, demonstrating that p53 is not required for a functional BER pathway, that the observed damage response is not part of the p53 response network, and that the BER intermediate-induced cytotoxic and genotoxic effects are distinct from the mechanism engaged in response to mismatch repair signaling. These studies demonstrate that, although base damage is repaired by the BER pathway, incomplete BER intermediates are shuttled into the homologous recombination pathway, suggesting possible coordination between BER and the recombination machinery.

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Section: Discussionmentioning

confidence: 93%

Base Excision Repair Intermediates Induce p53-independent Cytotoxic and Genotoxic Responses

Sobol

Kartalou

Almeida

et al. 2003

Journal of Biological Chemistry

171

158

View full text Add to dashboard Cite

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“…The membrane was hybridized with biotin-labeled strand-specific RNA probes and then hybridized with HRP-conjugated anti-streptavidin secondary antibody and developed with an ECL kit. RNA probes complementary to the transcribed or non-transcribed strand of the mouse DHFR gene were synthesized from plasmids pDKR25 and pDKR5 (kindly provided by Dr. Isabel Mellon, University of Kentucky), respectively (27). The quantity of DNA damage was determined by the ratio of the hybridization signal intensity in the T4 endonuclease V-treated DNA to the signal in the mock-treated DNA at each time point in each cell type.…”

Section: Methodsmentioning

confidence: 99%

Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

Liu

Yan

Lee

et al. 2011

Journal of Biological Chemistry

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Background: CSB, a member of the TC-NER pathway, is essential for UV light-induced DNA damage repair. Results: CSB expression is reduced in TR4-deficient tissues/cells, and restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Conclusion: TR4 modulates UV sensitivity via promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. Significance: Our findings may provide new information for the treatment of UV light-sensitive syndromes, skin cancer, and aging.

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“…The adducts formed by alkylating agents undergo DNA repair specific for the type of adduct. N-Alkylation products are repaired by nucleotide excision repair (NER) and base excision repair (BER) (Wiencke and Wiemels, 1995;Chaney and Sancar, 1996;Plosky et al, 2002;Drabløs et al, 2004). O 6 -Alkylguanine is repaired primarily by O 6 -alkylguanine-DNA alkyltransferase (MGMT; Esteller et al, 2000).…”

mentioning

confidence: 99%

Carmustine-Resistant Cancer Cells Are Sensitized to Temozolomide As A Result of Enhanced Mismatch Repair during the Development of Carmustine Resistance

Yamauchi

Ogawa²,

Ueda³

2008

Mol Pharmacol

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The cytotoxicity of the monofunctional alkylator temozolomide (TMZ) is mediated by mismatch repair (MMR) triggered by O 6 -alkylguanine, whereas MMR protects cells against bifunctional alkylators, including carmustine (BCNU). Therefore, TMZ may be cytotoxic to BCNU-resistant cancer cells because MMR affects sensitivity to TMZ and BCNU in a converse way. We evaluated TMZ cytotoxicity on BCNU-resistant variant (CEM-R) compared with the parental CCRF-CEM cell line (CEM-S). The mechanisms of its BCNU-resistance involved DNA repairs including nucleotide excision repair, base excision repair, alkylguanine alkyltransferase, MMR, and apoptotic and survival pathways. In particular, transcript levels of MMR-related hMLH1 and hMSH2 were enhanced in CEM-R cells. CEM-R cells were 8-fold more BCNU-resistant but surprisingly 9-fold more TMZ-sensitive than were CEM-S cells. Although TMZ-induced adducts include N-alkylated purines -alkylguanine. Cotreatment with cadmium chloride, an MMR inhibitor, disrupted the sensitivity of CEM-R cells to TMZ. The sensitivity to TMZ was reversed in the CEM-R variant clone that had been established by transfecting CEM-R cells with short hairpin hRNA against hMLH1, suggesting the critical role of MMR on sensitization to TMZ. In conclusion, BCNU-resistant CEM-R cells were sensitized to TMZ as a result of enhanced MMR during the development of BCNU resistance.

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Base excision repair and nucleotide excision repair contribute to the removal of N-methylpurines from active genes

Cited by 67 publications

References 51 publications

Base Excision Repair Intermediates Induce p53-independent Cytotoxic and Genotoxic Responses

Base Excision Repair Intermediates Induce p53-independent Cytotoxic and Genotoxic Responses

Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

Carmustine-Resistant Cancer Cells Are Sensitized to Temozolomide As A Result of Enhanced Mismatch Repair during the Development of Carmustine Resistance

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