Nucleotide Excision Repair in Eukaryotes
TL;DR: This review emphasizes biochemical, structural, cell biological, and genetic studies since 2005 that have shed light on many aspects of the NER pathway.
Abstract: Nucleotide excision repair (NER) is the main pathway used by mammals to remove bulky DNA lesions such as those formed by UV light, environmental mutagens, and some cancer chemotherapeutic adducts from DNA. Deficiencies in NER are associated with the extremely skin cancer-prone inherited disorder xeroderma pigmentosum. Although the core NER reaction and the factors that execute it have been known for some years, recent studies have led to a much more detailed understanding of the NER mechanism, how NER operates in the context of chromatin, and how it is connected to other cellular processes such as DNA damage signaling and transcription. This review emphasizes biochemical, structural, cell biological, and genetic studies since 2005 that have shed light on many aspects of the NER pathway.
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TL;DR: This introductory review will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue.
Abstract: Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235-263, 2017. © 2017 Wiley Periodicals, Inc.
954 citations
TL;DR: A mechanistic model is proposed that explains the complex genotype–phenotype correlations of transcription-coupled repair disorders and uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translated modifications, and the dynamic chromatin interactions that control its efficiency.
Abstract: Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype-phenotype correlations of transcription-coupled repair disorders.
889 citations
TL;DR: The essential factors and complexes involved in NER in humans are outlined, and additional factors and metabolic processes that affect the efficiency of this important process are commented on.
247 citations
TL;DR: The results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes and proposes that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes.
Abstract: UvrD helicase is required for nucleotide excision repair, although its role in this process is not well defined. Here we show that Escherichia coli UvrD binds RNA polymerase during transcription elongation and, using its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage. Our results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes. Furthermore, we show that the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair by promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions. Because backtracking is a shared feature of all cellular RNA polymerases, we propose that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes.
197 citations
TL;DR: The laboratory's findings on the molecular mechanisms by which MC1R signaling impacts NER are summarized and the structure and function of the receptor are reviewed.
Abstract: The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair, the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts nucleotide excision repair.
180 citations
Cites background from "Nucleotide Excision Repair in Eukar..."
...The NER pathway is the major means by which cells remove UV photoproducts from genomic DNA (reviewed in Scharer, 2013 and Shah and He, 2015) (Scharer, 2013; Shah and He, 2015)....
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References
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01 Jan 2006
TL;DR: Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in proKaryote Mutagenisation in eukaryotes Other DNA damage tolerance responses in eUKaryotes.
Abstract: DNA damage Mutations The reversal of base damage Base excision repair Nucleotide excision repair in prokaryotes Nucleotide excision repair in lower eukaryotes Nucleotide excision repair in mammalian cells: general considerations and chromatin dynamics Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in prokaryotes Mutagenesis in eukaryotes Other DNA damage tolerance responses in eukaryotes Hereditary diseases with defective responses to DNA damage
5,297 citations
"Nucleotide Excision Repair in Eukar..." refers background in this paper
...The transcription and NER factor TFIIH is the next factor to join the NER complex and it is recruited by direct interaction with the XPCRAD23B protein (Evans et al. 1997a; Yokoi et al. 2000; Araujo et al. 2001; Volker et al. 2001; Riedl et al. 2003; Friedberg et al. 2005)....
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...…Perspect Biol 2013;5:a012609 adducts formed by environmental mutagens such as benzo[a]pyrene or various aromatic amines, certain oxidative endogenous lesions such as cyclopurines and adducts formed by cancer chemotherapeutic drugs such as cisplatin (Friedberg et al. 2005; Gillet and Schärer 2006)....
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...The history of the discovery of NER, its association with genetic disorders, mechanistic features, and relationship with other cellular pathways has been extensively reviewed in 2005 in several articles in DNA Repair and Mutagenesis (Friedberg et al. 2005)....
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...At least two other disor- Editors: Errol C. Friedberg, Stephen J. Elledge, Alan R. Lehmann, Tomas Lindahl, and Marco Muzi-Falconi Additional Perspectives on DNA Repair, Mutagenesis, and Other Responses to DNA Damage available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012609 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a012609 1 ders, Cockayne syndrome and trichothiodystrophy (TTD), are also associated with defects in NER genes; but these patients do not present with skin cancer predisposition, but rather a host of developmental and neurological abnormalities (Lehmann 2003)....
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...adducts formed by environmental mutagens such as benzo[a]pyrene or various aromatic amines, certain oxidative endogenous lesions such as cyclopurines and adducts formed by cancer chemotherapeutic drugs such as cisplatin (Friedberg et al. 2005; Gillet and Schärer 2006)....
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TL;DR: The data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.
Abstract: The function of the ATR (ataxia-telangiectasia mutated- and Rad3-related)-ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication protein A (RPA), a protein complex that associates with single-stranded DNA (ssDNA), is required for the recruitment of ATR to sites of DNA damage and for ATR-mediated Chk1 activation in human cells. In vitro, RPA stimulates the binding of ATRIP to ssDNA. The binding of ATRIP to RPA-coated ssDNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the Rad17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-strand DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. Our data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.
2,632 citations
TL;DR: Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
Abstract: Normal skin fibroblasts can repair ultraviolet radiation damage to DNA by inserting new bases into DNA in the form of small patches. Cells from patients with the hereditary disease xeroderma pigmentosum carry a mutation such that repair replication of DNA is either absent or much reduced in comparison to normal fibroblasts. Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
1,649 citations
Additional excerpts
...The gap-filling step in NER can be monitored by unscheduled DNA synthesis (UDS), and this assay allowed the connection between NER and the genetic disorder xeroderma pigmentusum (XP) to be made (Cleaver 1968)....
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TL;DR: Finite cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.
Abstract: Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.
960 citations
"Nucleotide Excision Repair in Eukar..." refers background in this paper
...NER can be initiated by two subpathways: global genome NER (GG-NER) or transcription-coupled NER (TC-NER; Gillet and Schärer 2006; Hanawalt and Spivak 2008)....
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...NER can be initiated by two subpathways: global genome NER (GG-NER) or transcription-coupled NER (TC-NER; Gillet and Schärer 2006; Hanawalt and Spivak 2008)....
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TL;DR: The onset of DNA synthesis is associated with thymine dimer removal, which is suggested to be one step in cell recovery in resistant strains of E. coli.
Abstract: The state of thymine dimers during the time in which resistant strains of Escherichia coli recover from uvinduced delays in DNA synthesis was investigated. Five strains of E. coli were labeled by growth in Mg medium containing tritiated thymidine. At various times after uv irradiation (200 ergs/ mm2 at 265 m μ ), 1 ml aliquots of cell suspension were centrifuged, trichloracetic acid (TCA) supernatants were removed, and samples were prepared for chromatographic and counting procedures. Photoreactivating illumination was provided by black-light lamps. The radiation dose used stopped DNA synthesis and virtually eliminated colony-formation in two of the five strains. In the other three strains DNA synthesis was inhibited for 60 minutes and colony formation yields were reduced to 0.1 to 10 percent. The dimers disappeared from the acid- soluble fraction of the cells and appeared in the oligonucleotides. In a sensitive strain the dimers remained in the insoluble phase and were photoreactivable. Thus, the onset of DNA synthesis is associated with thymine dimer removal, which is suggested to be one step in cell recovery.
953 citations