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Journal of Zhejiang University.... Jan 2021Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation... (Review)
Review
Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase (MGMT), and dealkylation by the AlkB homolog (ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.
Topics: AlkB Homolog 1, Histone H2a Dioxygenase; Alkylating Agents; Alkylation; DNA Adducts; DNA Damage; DNA Glycosylases; DNA Mismatch Repair; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Humans; Models, Biological; Neoplasms; Tumor Suppressor Proteins
PubMed: 33448187
DOI: 10.1631/jzus.B2000344 -
International Journal of Molecular... Feb 2023Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as... (Review)
Review
Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.
Topics: Nitrosamines; DNA Damage; Alkylation; DNA Repair; Alkylating Agents; DNA Adducts
PubMed: 36902118
DOI: 10.3390/ijms24054684 -
Trends in Biochemical Sciences Mar 2017Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are... (Review)
Review
Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so-called 'epigenetic' adducts. Here, we discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy.
Topics: Alkylation; Antineoplastic Agents, Alkylating; DNA Damage; DNA Repair; DNA, Neoplasm; Humans; Neoplasms
PubMed: 27816326
DOI: 10.1016/j.tibs.2016.10.001 -
BioEssays : News and Reviews in... Jun 1995Current pharmacopoeias invariably refer to a category of 'alkylating drugs', still among the most widely used in cancer chemotherapy. They are described as acting... (Review)
Review
Current pharmacopoeias invariably refer to a category of 'alkylating drugs', still among the most widely used in cancer chemotherapy. They are described as acting through their ability to damage DNA, thus interfering with cell replication. Unfortunately, this mode of action implicates these drugs as carcinogens. Thus the early studies recalled in this essay proved to be relevant to our understanding of both the main problems with which cancer research concerns itself: the causation of cancer and possible methods of treatment of this group of diseases.
Topics: Alkylating Agents; Alkylation; Animals; Antineoplastic Agents, Alkylating; Carcinogens; DNA; DNA Damage; Humans; Neoplasms; Structure-Activity Relationship
PubMed: 7575500
DOI: 10.1002/bies.950170615 -
Critical Reviews in Biochemistry and... Apr 2021DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are... (Review)
Review
DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are deeply entwined with the development of poisonous materials originally intended for use in warfare. Over the last decades, their anti-proliferative effects have focused on the specific mechanisms by which they damage DNA, and the factors involved in the repair of such damage. Due to the variety of aberrant adducts created even for the simplest alkylating agents, numerous pathways of repair are engaged as a defense against this damage. More recent work has underscored the role of RNA damage in the cellular response to these agents, although the understanding of their role in relation to established DNA repair pathways is still in its infancy. In this review, we discuss the chemistry of alkylating agents, the numerous ways in which they damage nucleic acids, as well as the specific DNA and RNA repair pathways which are engaged to counter their effects.
Topics: Alkylating Agents; Alkylation; Animals; DNA; DNA Damage; DNA Repair; Humans; RNA
PubMed: 33430640
DOI: 10.1080/10409238.2020.1869173 -
Mutation Research 2013Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a... (Review)
Review
Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a complex cellular response. After DNA damage, cells trigger a series of signaling cascades promoting cellular survival and cell cycle blockage which enables time for DNA repair to occur. More recently, induction of autophagy has been observed in cancer cells after treatment with different DNA-targeted anticancer drugs, including alkylating agents. Several studies have demonstrated that induction of autophagy after DNA damage delays apoptotic cell death and may therefore lead to chemoresistance, which is the limiting factor for successful chemotherapy. On the other hand, depending on the extent of damage and the cellular context, the induction of autophagy may also contribute to cell death. Given these conflicting results, many studies have been conducted to better define the role of autophagy in cancer cells in response to chemotherapy. In this review, we describe the main alkylating agents used in clinical oncology as well as the cellular response they evoke with emphasis on autophagy.
Topics: Alkylating Agents; Alkylation; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Autophagy; DNA Damage; Humans
PubMed: 23872363
DOI: 10.1016/j.mrrev.2013.07.001 -
Redox Biology May 2022Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely...
Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely unknown. Here we found that stabilization of the mismatch repair (MMR) protein MSH6 in response to alkylation damage requires interactions with the molybdopterin synthase associating complex (MPTAC) and Ada2a-containing histone acetyltransferase complex (ATAC). Furthermore, MSH6 promotes sterol biosynthesis via the mevalonate pathway in a MPTAC- and ATAC-dependent manner. MPTAC reduces the source of alkylating agents (ROS). Therefore, the association between MMR proteins, MPTAC, and ATAC promotes anti-inflammation response and reduces alkylating agents. The inflammatory responses measured by xanthine oxidase activity are elevated in Lymphoblastoid Cell Lines (LCLs) from some Fragile X-associated disorders (FXD) patients, suggesting that alkylating agents are increased in these FXD patients. However, MPTAC is disrupted in LCLs from some FXD patients. In LCLs from other FXD patients, interaction between MSH6 and ATAC was lost, destabilizing MSH6. Thus, impairment of MPTAC and ATAC may cause alkylation damage resistance in some FXD patients.
Topics: Alkylating Agents; Alkylation; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Reactive Oxygen Species; Sterols
PubMed: 35189552
DOI: 10.1016/j.redox.2022.102270 -
Methods in Molecular Biology (Clifton,... 2019Reduction and alkylation are common processing steps in sample preparation for qualitative and quantitative proteomic analyses. In principle, these steps mitigate the... (Review)
Review
Reduction and alkylation are common processing steps in sample preparation for qualitative and quantitative proteomic analyses. In principle, these steps mitigate the limitations resulting from the presence of disulfide bridges. There has been recurring debate in the proteomics community around their use, with concern over negative impacts that result from overalkylation (off-target, non-thiol sites) or incomplete reduction and/or S-alkylation of cysteine. This chapter integrates findings from a number of studies on different reduction and alkylation strategies, to guide users in experimental design for their optimal use in proteomic workflows.
Topics: Alkylating Agents; Alkylation; Cysteine; Oxidation-Reduction; Protein Processing, Post-Translational; Proteomics; Reducing Agents; Workflow
PubMed: 30980324
DOI: 10.1007/978-1-4939-9232-4_7 -
DNA Repair Nov 2004Alkylation lesions in DNA and RNA result from endogenous compounds, environmental agents and alkylating drugs. Simple methylating agents, e.g. methylnitrosourea,... (Review)
Review
Alkylation lesions in DNA and RNA result from endogenous compounds, environmental agents and alkylating drugs. Simple methylating agents, e.g. methylnitrosourea, tobacco-specific nitrosamines and drugs like temozolomide or streptozotocin, form adducts at N- and O-atoms in DNA bases. These lesions are mainly repaired by direct base repair, base excision repair, and to some extent by nucleotide excision repair (NER). The identified carcinogenicity of O(6)-methylguanine (O(6)-meG) is largely caused by its miscoding properties. Mutations from this lesion are prevented by O(6)-alkylG-DNA alkyltransferase (MGMT or AGT) that repairs the base in one step. However, the genotoxicity and cytotoxicity of O(6)-meG is mainly due to recognition of O(6)-meG/T (or C) mispairs by the mismatch repair system (MMR) and induction of futile repair cycles, eventually resulting in cytotoxic double-strand breaks. Therefore, inactivation of the MMR system in an AGT-defective background causes resistance to the killing effects of O(6)-alkylating agents, but not to the mutagenic effect. Bifunctional alkylating agents, such as chlorambucil or carmustine (BCNU), are commonly used anti-cancer drugs. DNA lesions caused by these agents are complex and require complex repair mechanisms. Thus, primary chloroethyl adducts at O(6)-G are repaired by AGT, while the secondary highly cytotoxic interstrand cross-links (ICLs) require nucleotide excision repair factors (e.g. XPF-ERCC1) for incision and homologous recombination to complete repair. Recently, Escherichia coli protein AlkB and human homologues were shown to be oxidative demethylases that repair cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) residues. Numerous AlkB homologues are found in viruses, bacteria and eukaryotes, including eight human homologues (hABH1-8). These have distinct locations in subcellular compartments and their functions are only starting to become understood. Surprisingly, AlkB and hABH3 also repair RNA. An evaluation of the biological effects of environmental mutagens, as well as understanding the mechanism of action and resistance to alkylating drugs require a detailed understanding of DNA repair processes.
Topics: AlkB Homolog 1, Histone H2a Dioxygenase; Alkylating Agents; Alkylation; Amino Acid Sequence; Animals; Carcinogens; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; Escherichia coli Proteins; Humans; Mixed Function Oxygenases; Models, Biological; Molecular Sequence Data; Neoplasms; Phylogeny; RNA; Sequence Homology, Amino Acid
PubMed: 15380096
DOI: 10.1016/j.dnarep.2004.05.004 -
Environmental and Molecular Mutagenesis 1988Treatment of cells with low levels of alkylating agents for extended periods of time causes them to become resistant to the lethal and mutagenic effects of subsequent... (Review)
Review
Treatment of cells with low levels of alkylating agents for extended periods of time causes them to become resistant to the lethal and mutagenic effects of subsequent high-level challenge treatments with alkylating agents. This increased resistance has been called the adaptive response to alkylation damage and results from the induction of an alkylation-specific DNA repair response. The adaptive response is most efficiently induced by methylating agents and is most effective against the lethal and mutagenic effects of methylation damage to DNA. Four genes have been identified as components of this response, ada, alkA, alkB and aidB. The functions of two of these genes are known. AlkA protein functions as a glycosylase that repairs N3-meA, N3-meG, O2-meT, and O2-meC residues in DNA, and Ada protein functions as an alkyltransferase that removes alkyl groups from O6-meG, O4-meT residues as well as methylphosphotriesters. After it interacts with methylated DNA, Ada protein functions as a positive regulatory element that controls the expression of the adaptive response by stimulating the expression of the ada-alkB operon, and the alkA and aidB genes.
Topics: Alkylating Agents; Alkylation; Bacterial Proteins; DNA Damage; DNA Repair; DNA, Bacterial; Drug Resistance, Microbial; Escherichia coli; Genes, Bacterial; Methylation; SOS Response, Genetics
PubMed: 3278898
DOI: 10.1002/em.2850110210