Search results for "Repair"
showing 10 items of 747 documents
Transgenic systems in studies on genotoxicity of alkylating agents: critical lesions, thresholds and defense mechanisms
1998
Abstract Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also…
Assessment of mechanisms driving non-linear dose-response relationships in genotoxicity testing.
2014
In genetic toxicology, risk assessment has traditionally adopted linear dose-responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non-linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose me…
Human Monocytes, but not Dendritic Cells Derived from Them, Are Defective in Base Excision Repair and Hypersensitive to Methylating Agents
2007
Abstract Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N′-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other …
Kinetics of gamma-H2AX focus formation upon treatment of cells with UV light and alkylating agents.
2008
Histone H2AX is rapidly phosphorylated in response to DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). Here we show that DNA damage induced by alkylating agents [methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] and ultraviolet light (UV-C) leads to a dose and time dependent accumulation of phosphorylated H2AX (gamma-H2AX). Time course experiments revealed that the number of gamma-H2AX foci reached peak levels 8 hr after MMS or MNNG treatment and declined to almost control values within 24 hr after exposure. Upon UV-C treatment, a biphasic response was observed with a maximum 12 hr after treatment. In 43-3B cells deficient in nucleotide excisi…
MGMT: Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents
2007
O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against alkylating agents that generate, among other lesions, O(6)-alkylguanine in DNA (collectively termed O(6)-alkylating agents [O(6)AA]). The defense is highly important, since O(6)AA are common environmental carcinogens, are formed endogenously during normal cellular metabolism and possibly inflammation, and are being used in cancer therapy. O(6)AA induced DNA damage is subject to repair, which is executed by MGMT, AlkB homologous proteins (ABH) and base excision repair (BER). Although this review focuses on MGMT, the mechanism of repair by ABH and BER will also be discussed. Experimental systems, in wh…
Primary mouse fibroblasts deficient for c-Fos, p53 or for both proteins are hypersensitive to UV light and alkylating agent-induced chromosomal break…
2000
The important regulatory proteins, c-Fos and p53 are induced by exposure of cells to a variety of DNA damaging agents. To investigate their role in cellular defense against genotoxic compounds, we comparatively analysed chromosomal aberrations and apoptosis induced by ultraviolet (UV-C) light and the potent alkylating agent methyl methanesulfonate (MMS) in primary diploid mouse fibroblasts knockout for either c-Fos or p53, or double knockout for both genes. We show that c-Fos and p53 deficient fibroblasts are more sensitive than the corresponding wild-type cells as to the induction of chromosomal aberrations and apoptosis. Double knockout fibroblasts lacking both c-Fos and p53 are viable an…
Mismatch G-T binding activity and MSH2 expression is quantitatively related to sensitivity of cells to methylating agents
1998
To elucidate mechanisms involved in alkylating drug resistance, Chinese hamster cells resistant to methylating agents have been generated upon transfection with human DNA. Here it is shown that these Chinese hamster ovary (CHO) variants exhibit the tolerance phenotype: they are alkyltransferase deficient (Mex-), cross-resistant to 6-thioguanine, exhibit reduced G-T binding (MutS alpha) activity and express the mismatch repair protein MSH2 at a significantly lower level than the corresponding control. By comparing wild-type cells with different tolerant strains that show gradual differences in resistance to methylating agents, it was shown that both the G-T binding activity and the amount of…
Towards an ideal source of mesenchymal stem cell isolation for possible therapeutic application in regenerative medicine.
2014
Background. The possibility of obtaining mesenchymal stem cells (MSCs) from fetal tissue such as amniotic fluid, chorionic villi and placenta is well-known and a comparison between MSCs originating in different sources such as fetal tissue and those from bone marrow in terms of yield and function is a topical issue. The mesenchymal stem cells isolated from bone marrow are well-characterized. Unfortunately the low quantitative yield during isolation is a major problem. For this reason, other tissue sources for MSCs are of paramount importance. Conclusion. In this review, starting from a description of the molecular and cellular biology of MSCs, we describe alternative sources of isolation ot…
Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair
2021
Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocyc…
Influence of DNA damage and repair upon the risk of treatment related leukemia
2008
Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) are malignancies occurring after exposure to chemotherapy and/or radiotherapy. Several studies have addressed cumulative dose, dose intensity and exposure to specific agents of preceding cytotoxic therapy in relation to the risk of developing such leukemia. Since only a small percentage of patients exposed to cytotoxic therapy develop t-MDS/AML, it has been suggested that some genetic predisposition may be involved, specifically associated to polymorphisms in certain genes involved in chemotherapy/radiotherapy response - fundamentally genes intervening in drug detoxification and DNA synthesis and repair. A review is made …