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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 -
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 -
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 -
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 -
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 -
Biochemical and Biophysical Research... Jan 2021DNA integrity is challenged by both exogenous and endogenous alkylating agents. DNA repair proteins such as Escherichia coli AlkB family of enzymes can repair...
DNA integrity is challenged by both exogenous and endogenous alkylating agents. DNA repair proteins such as Escherichia coli AlkB family of enzymes can repair 1-methyladenine and 3-methylcytosine adducts by oxidative demethylation. Human AlkB homologue 5 (ALKBH5) is RNA N6-methyladenine demethylase and not known to be involved in DNA repair. Herein we show that ALKBH5 also has weak DNA repair activity and it can demethylate DNA 3-methylcytosine. The mutation of the amino acid residues involved in demethylation also abolishes the DNA repair activity of ALKBH5. Overexpression of ALKBH5 decreases the 3-methylcytosine level in genomic DNA and reduces the cytotoxic effects of the DNA damaging alkylating agent methyl methanesulfonate. Thus, demethylation by ALKBH5 might play a supporting role in maintaining genome integrity.
Topics: AlkB Homolog 5, RNA Demethylase; Alkylating Agents; Cytosine; DNA Adducts; DNA Damage; DNA Methylation; DNA Repair; Demethylation; HEK293 Cells; Humans; Mesylates
PubMed: 33321288
DOI: 10.1016/j.bbrc.2020.12.017 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2021Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as...
Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
Topics: Alkylation; Chlorambucil; DNA; Imidazoles; Nylons; Pyrroles
PubMed: 33145851
DOI: 10.1002/chem.202004421 -
International Journal of Molecular... Nov 2015DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation;... (Review)
Review
DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.
Topics: Alkylating Agents; Alkylation; Cell Nucleus; Cytoplasm; DNA; DNA Adducts; DNA Damage; DNA Replication; DNA-Binding Proteins; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Nucleic Acid Conformation; Protein Binding; Transcription Factors
PubMed: 26556350
DOI: 10.3390/ijms161125971 -
Molecules (Basel, Switzerland) Sep 2022DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA... (Review)
Review
DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.
Topics: Alkylating Agents; Biological Products; Biosynthetic Pathways; DNA
PubMed: 36234921
DOI: 10.3390/molecules27196387