Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins (original) (raw)
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The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage
Nucleic Acids Research, 2020
The six major mammalian DNA repair pathways were discovered as independent processes, each dedicated to remove specific types of lesions, but the past two decades have brought into focus the significant interplay between these pathways. In particular, several studies have demonstrated that certain proteins of the nucleotide excision repair (NER) and base excision repair (BER) pathways work in a cooperative manner in the removal of oxidative lesions. This review focuses on recent data showing how the NER proteins, XPA, XPC, XPG, CSA, CSB and UV-DDB, work to stimulate known glycosylases involved in the removal of certain forms of base damage resulting from oxidative processes, and also discusses how some oxidative lesions are probably directly repaired through NER. Finally, since many glycosylases are inhibited from working on damage in the context of chromatin, we detail how we believe UV-DDB may be the first responder in altering the structure of damage containing-nucleosomes, allow...
Toxicology, 2003
The DNA base excision repair (BER) is a ubiquitous mechanism for removing damage from the genome induced by spontaneous chemical reaction, reactive oxygen species (ROS) and also DNA damage induced by a variety of environmental genotoxicants. DNA repair is essential for maintaining genomic integrity. As we learn more about BER, a more complex mechanism emerges which supersedes the classical, simple pathway requiring only four enzymatic reactions. The key to understand the complete BER process is to elucidate how multiple proteins interact with one another in a coordinated process under specific physiological conditions.
Base Excision Repair and Lesion-Dependent Subpathways for Repair of Oxidative DNA Damage
Antioxidants & Redox Signaling, 2011
Nuclear and mitochondrial genomes are under continuous assault by a combination of environmentally and endogenously derived reactive oxygen species, inducing the formation and accumulation of mutagenic, toxic, and=or genome-destabilizing DNA lesions. Failure to resolve these lesions through one or more DNA-repair processes is associated with genome instability, mitochondrial dysfunction, neurodegeneration, inflammation, aging, and cancer, emphasizing the importance of characterizing the pathways and proteins involved in the repair of oxidative DNA damage. This review focuses on the repair of oxidative damage-induced lesions in nuclear and mitochondrial DNA mediated by the base excision repair (BER) pathway in mammalian cells. We discuss the multiple BER subpathways that are initiated by one of 11 different DNA glycosylases of three subtypes: (a) bifunctional with an associated b-lyase activity; (b) monofunctional; and (c) bifunctional with an associated b,dlyase activity. These three subtypes of DNA glycosylases all initiate BER but yield different chemical intermediates and hence different BER complexes to complete repair. Additionally, we briefly summarize alternate repair events mediated by BER proteins and the role of BER in the repair of mitochondrial DNA damage induced by ROS. Finally, we discuss the relation of BER and oxidative DNA damage in the onset of human disease. Antioxid. Redox
DNA Oxidation and Excision Repair Pathways
International Journal of Molecular Sciences
The physiological impact of the aberrant oxidation products on genomic DNA were demonstrated by embryonic lethality or the cancer susceptibility and/or neurological symptoms of animal impaired in the base excision repair (BER); the major pathway to maintain genomic integrity against non-bulky DNA oxidation. However, growing evidence suggests that other DNA repair pathways or factors that are not primarily associated with the classical BER pathway are also actively involved in the mitigation of oxidative assaults on the genomic DNA, according to the corresponding types of DNA oxidation. Among others, factors dedicated to lesion recognition in the nucleotide excision repair (NER) pathway have been shown to play eminent roles in the process of lesion recognition and stimulation of the enzyme activity of some sets of BER factors. Besides, substantial bulky DNA oxidation can be preferentially removed by a canonical NER mechanism; therefore, loss of function in the NER pathway shares comm...
Nucleotide Incision Repair: An Alternative and Ubiquitous Pathway to Handle Oxidative DNA Damage
Oxidative Damage to Nucleic Acids, 2007
A erobic respiration and exogenous factors such as ionizing radiation and drugs generate reactive oxygen species (ROS). DNA has limited chemical stability and it is one of the most biologically important targets of ROS. 1 Oxidative DNA lesions are believed to be a major type of endogenous damage leading to human degenerative disorders including cancer, cardiovascular disease and brain dysfunction. The clinical features of inherited human DNA repair deficiency disorders such as Cockayne syndrome and Fanconi's anemia point to the complex nature of endogenous oxidative DNA damage which may include bulky adducts, interstrand crosslinks and clustered lesions. Oxidized DNA bases are substrates for two overlapping pathways: base excision repair (BER) and nucleotide incision repair (NIR). In the BER pathway, a DNA glycosylase cleaves the N-glycosylic bond between the modified base and deoxyribose, leaving either an abasic site or a single-strand break in DNA. 2 Alternatively, in the NIR pathway, an apurinic/apyrimidinic (AP) endonuclease incises oxidatively damaged DNA in a DNA glycosylase-independent manner, providing the correct ends for DNA synthesis, coupled to the repair of the remaining 5´-dangling modified nucleotide. We have demonstrated that the major human apurinic/ apyrimidinic (AP) endonuclease (Ape1) is involved in the NIR pathway. 4 NIR and BER pathways share many common substrates suggesting that they work in concert to cleanse genomic DNA of potentially mutagenic and cytotoxic lesions. Recently, we have genetically separated AP endonuclease and nucleotide incision activities to demonstrate that NIR handles a distinct type of oxidative DNA damage that cannot be processed in the BER pathway. The aim of this review is to summarise the present knowledge about the alternative DNA repair pathways for oxidised base modifications.
The eukaryotic nucleotide excision repair pathway
Biochimie, 2003
Nucleotide excision repair (NER) is the most versatile mechanism of DNA repair, recognizing and dealing with a variety of helix-distorting lesions, such as the UV-induced photoproducts cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4 PPs). In this review, we describe the main protein players and the different sequential steps of the eukaryotic NER mechanism in human cells, from lesion recognition to damage removal and DNA synthesis. Studies on the dynamics of protein access to the damaged site, and the kinetics of lesion removal contribute to the knowledge of how the cells respond to genetic insult. DNA lesions as well as NER factors themselves are also implicated in changes in cell metabolism, influencing cell cycle progression or arrest, apoptosis and genetic instability. These changes are related to increased mutagenesis and carcinogenesis. Finally, the recent collection of genomic data allows one to recognize the high conservation and the evolution of eukaryotic NER. The distribution of NER orthologues in different organisms, from archaea to the metazoa, displays challenging observations. Some of NER proteins are widespread in nature, probably representing ancient DNA repair proteins, which are candidates to participate in a primitive NER mechanism.
Oxidative Medicine and Cellular Longevity
The continuous exposure of the human body’s cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER’s activity. These modulators, particularly the ...