Search results for "DNA Repair Enzyme"
showing 10 items of 34 documents
The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Defic…
2007
Abstract Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csbm/m/Ogg1−/− mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csbm/m/Ogg1−/− mice and repair-proficient controls with the peroxisome proliferator WY-14…
Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53
2009
Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O(6)-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol m…
MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and …
2010
The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a key player in tumor cell resistance. Promoter methylation, MGMT activity and immunohistochemistry are used for determining the MGMT status. However, it is unclear whether MGMT promoter methylation correlates with MGMT activity and whether MGMT promoter methylation of the pretreatment tumor predicts the MGMT status of recurrences. To address these questions, we determined MGMT activity promoter methylation and immunoreactivity in pretreatment and recurrent glioblastomas (GB, WHO Grade IV), and in astrocytomas (WHO Grade III). We show that GB that were promoter methylated display a range of 0-62 fmol/mg MGMT and tumor…
Novel Approaches for Glioblastoma Treatment: Focus on Tumor Heterogeneity, Treatment Resistance, and Computational Tools
2019
BACKGROUND: Glioblastoma (GBM) is a highly aggressive primary brain tumor. Currently, the suggested line of action is the surgical resection followed by radiotherapy and treatment with the adjuvant temozolomide (TMZ), a DNA alkylating agent. However, the ability of tumor cells to deeply infiltrate the surrounding tissue makes complete resection quite impossible, and in consequence, the probability of tumor recurrence is high, and the prognosis is not positive. GBM is highly heterogeneous and adapts to treatment in most individuals. Nevertheless, these mechanisms of adaption are unknown. RECENT FINDINGS: In this review, we will discuss the recent discoveries in molecular and cellular heterog…
Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence
2020
AbstractTranscriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-me…
Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents
2000
Mammalian mismatch repair has been implicated in mismatch correction, the prevention of mutagenesis and cancer, and the induction of genotoxicity and apoptosis. Here, we show that treatment of cells specifically with agents inducing O(6)-methylguanine in DNA, such as N-methyl-N'-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea, elevates the level of MSH2 and MSH6 and increases GT mismatch binding activity in the nucleus. This inducible response occurs immediately after alkylation, is long-lasting and dose-dependent, and results from translocation of the preformed MutSalpha complex (composed of MSH2 and MSH6) from the cytoplasm into the nucleus. It is not caused by an increase in MSH2 gen…
Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein
2003
Activation of poly(ADP-ribose)polymerases 1 and 2 (PARP-1 and PARP-2) is one of the earliest responses of mammalian cells to DNA damage by numerous genotoxic agents. We have analysed the influence of PARP inhibition, either achieved by over-expression of the DNA binding domain of PARP-1 or by treatment with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone, on the repair of single-strand breaks (SSB), pyrimidine dimers and oxidative base modifications sensitive to Fpg protein (mostly 8-hydroxyguanine) in mammalian cells at very low, non-cytotoxic levels of DNA damage. The data show that the repair rates of all three types of DNA damage are significantly lower in PARP-inhibited c…
APE/Ref-1 and the mammalian response to genotoxic stress.
2003
Human apurinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative or alkylating compounds as well as in the regulation of stress inducible transcription factors such as AP-1, NF-kappaB, HIF-1 and p53. With respect to transcriptional regulation, both redox dependent and independent mechanisms have been described. APE/Ref-1 also acts as a transcriptional repressor. Recent data indicate that APE/Ref-1 negatively regulates the activity of the Ras-related GTPase Rac1. How these different physiological activities of APE/Ref-1 are coordinated is poorly understood. So far, convincing evidence is available that the ex…
Cockayne syndrome: varied requirement of transcription-coupled nucleotide excision repair for the removal of three structurally different adducts fro…
2014
Hereditary defects in the transcription-coupled nucleotide excision repair (TC-NER) pathway of damaged DNA cause severe neurodegenerative disease Cockayne syndrome (CS), however the origin and chemical nature of the underlying DNA damage had remained unknown. To find out, to which degree the structural properties of DNA lesions determine the extent of transcription arrest in human CS cells, we performed quantitative host cell reactivation analyses of expression vectors containing various synthetic adducts. We found that a single 3-(deoxyguanosin-N 2-yl)-2-acetylaminofluorene adduct (dG(N 2)-AAF) constitutes an unsurmountable obstacle to transcription in both CS-A and CS-B cells and is remov…
Late activation of stress kinases (SAPK/JNK) by genotoxins requires the DNA repair proteins DNA-PKcs and CSB.
2005
Although genotoxic agents are powerful inducers of stress kinases (SAPK/JNK), the contribution of DNA damage itself to this response is unknown. Therefore, SAPK/JNK activation of cells harboring specific defects in DNA damage-recognition mechanisms was studied. Dual phosphorylation of SAPK/JNK by the genotoxin methyl methanesulfonate (MMS) occurred in two waves. The early response (≤2 h after exposure) was similar in cells knockout for ATM, PARP, p53, and CSB or defective in DNA-PKcscompared with wild-type cells. The late response however (≥4 h), was drastically reduced in DNA-PKcsand Cockayne's syndrome B (CSB)-deficient cells. Similar results were obtained with human cells lacking DNA-PKc…