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Samuel H. Wilson - One of the best experts on this subject based on the ideXlab platform.
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Base-Excision Repair: Role of DNA Polymerase β in Late-Stage Base Excision Repair
Chemical Carcinogenesis, 2010Co-Authors: Kenjiro Asagoshi, Samuel H. WilsonAbstract:The cellular DNA Repair pathway known as Base-Excision Repair is responsible for removing toxic Base lesions and strand breaks from genomic and mitochondrial DNA. The Base-Excision Repair pathway is conserved in organisms throughout nature, but there are many variations probably reflecting the broad range of genotoxic stresses encountered and the gene expression status of the organism. There has been remarkable progress in recent years toward deciphering the various types of Base lesions and the multiple steps and subpathways involved in the overall Base Excision pathway. This progress is reviewed here, and a detailed discussion of current research on the long-patch Base-Excision Repair subpathway is presented.
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HMGB1: roles in Base Excision Repair and related function.
Biochimica et Biophysica Acta, 2010Co-Authors: Yuan Liu, Rajendra Prasad, Samuel H. WilsonAbstract:High mobility group box 1 (HMGB1) is a nonhistone architectural protein that is involved in many biological processes including chromatin remodeling, transcription, cell signaling of inflammation, DNA damage Repair and others. Recent studies have identified the cross-link of HMGB1 with a DNA Base Excision Repair intermediate indicating that this protein is involved in Base Excision Repair (BER) pathway. Further characterization of the roles of HMGB1 in BER demonstrates that the protein acts as a cofactor to regulate BER sub-pathways by inhibiting single-nucleotide BER and stimulating long-patch BER through modulating the activities of Base Excision Repair enzymes. Directing of Base lesion Repair to the long-patch sub-pathway can result in trinucleotide repeat instability suggesting an important role of HMGB1 in modulating genome stability.
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eLS - Base Excision Repair, AP Endonucleases and DNA Glycosylases
Encyclopedia of Life Sciences, 2005Co-Authors: Miriam Sander, Samuel H. WilsonAbstract:Base Excision Repair is an important cellular mechanism that protects the integrity of DNA by Repairing damage caused by alkylating agents and reactive oxygen species. The altered DNA Base, and in some cases a few nucleotides adjacent to the altered Base, is removed by Excision, and the DNA is Repaired by DNA synthesis and ligation. Keywords: DNA Repair; DNA damage; mutation; polymerase; nuclease
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Passing the baton in Base Excision Repair.
Nature structural biology, 2000Co-Authors: Samuel H. Wilson, Thomas A. KunkelAbstract:Apurinic/apyrmidinic endonuclease 1 (APE1) plays a central role in DNA Repair by cleaving the DNA backbone 5′ of AP sites that result from removal of damaged Bases. New structural findings on APE1–DNA cocrystals provide insights into how this enzyme binds and cleaves its substrate and how, like one member in an efficient relay team, it coordinates potentially dangerous steps in the Base Excision Repair pathway.
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Up-regulation of Base Excision Repair correlates with enhanced protection against a DNA damaging agent in mouse cell lines
Nucleic acids research, 1998Co-Authors: Kuang-hua Chen, Robert W. Sobol, Julie K Horton, Rakesh K Singhal, F. Michael Yakes, Deepak Srivastava, Bennett Van Houten, Samuel H. WilsonAbstract:DNA polymerase beta is required in mammalian cells for the predominant pathway of Base Excision Repair involving single nucleotide gap filling DNA synthesis. Here we examine the relationship between oxidative stress, cellular levels of DNA polymerase beta and Base Excision Repair capacity in vitro , using mouse monocytes and either wild-type mouse fibroblasts or those deleted of the DNA polymerase beta gene. Treatment with an oxidative stress-inducing agent such as hydrogen peroxide, 3-morpholinosydnonimine, xanthine/xanthine oxidase or lipopolysaccharide was found to increase the level of DNA polymerase beta in both monocytes and fibroblasts. Base Excision Repair capacity in vitro , as measured in crude cell extracts, was also increased by lipopolysaccharide treatment in both cell types. In monocytes lipopolysaccharide-mediated up-regulation of the Base Excision Repair system correlated with increased resistance to the monofunctional DNA alkylating agent methyl methanesulfonate. By making use of a quantitative PCR assay to detect lesions in genomic DNA we show that lipopolysaccharide treatment of fibroblast cells reduces the incidence of spontaneous DNA lesions. This effect may be due to the enhanced DNA polymerase beta-dependent Base Excision Repair capacity of the cells, because a similar decrease in DNA lesions was not observed in cells deficient in Base Excision Repair by virtue of DNA polymerase beta gene deletion. Similarly, fibroblasts treated with lipopolysaccharide were more resistant to methyl methanesulfonate than untreated cells. This effect was not observed in cells deleted of the DNA polymerase beta gene. These results suggest that the DNA polymerase beta-dependent Base Excision Repair pathway can be up-regulated by oxidative stress-inducing agents in mouse cell lines.
G Murcia - One of the best experts on this subject based on the ideXlab platform.
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Base Excision Repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1
Biochemistry, 2000Co-Authors: F Dantzer, G De La Rubia, J Ménissier-de Murcia, G Murcia, Z Hostomsky, V SchreiberAbstract:In mammalian cells, damaged Bases in DNA are corrected by the Base Excision Repair pathway which is divided into two distinct pathways depending on the length of the resynthesized patch, replacement of one nucleotide for short-patch Repair, and resynthesis of several nucleotides for long-patch Repair. The involvement of poly(ADP-ribose) polymerase-1 (PARP-1) in both pathways has been investigated by using PARP-1-deficient cell extracts to Repair single abasic sites derived from uracil or 8-oxoguanine located in a double-stranded circular plasmid. For both lesions, PARP-1-deficient cell extracts were about half as efficient as wild-type cells at the polymerization step of the short-patch Repair synthesis, but were highly inefficient at the long-patch Repair. We provided evidence that PARP-1 constitutively interacts with DNA polymerase beta. Using cell-free extracts from mouse embryonic cells deficient in DNA polymerase beta, we demonstrated that DNA polymerase beta is involved in the Repair of uracil-derived AP sites via both the short and the long-patch Repair pathways. When both PARP-1 and DNA polymerase beta were absent, the two Repair pathways were dramatically affected, indicating that Base Excision Repair was highly inefficient. These results show that PARP-1 is an active player in DNA Base Excision Repair.
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Involvement of poly(ADP-ribose) polymerase in Base Excision Repair
Biochimie, 1999Co-Authors: F Dantzer, V Schreiber, C Niedergang, C Trucco, E Flatter, G De La Rubia, J Oliver, V Rolli, J Ménissier-de Murcia, G MurciaAbstract:Poly(ADP-ribose) polymerase (PARP) is a zinc-finger DNA binding protein that detects and signals DNA strand breaks generated directly or indirectly by genotoxic agents. In response to these lesions, the immediate poly(ADP-ribosylation) of nuclear proteins converts DNA interruptions into intracellular signals that activate DNA Repair or cell death programs. To elucidate the biological function of PARP in vivo, the mouse PARP gene was inactivated by homologous recombination to generate mice lacking a functional PARP gene. PARP knockout mice and the derived mouse embryonic fibroblasts (MEFs) were acutely sensitive to monofunctional alkylating agents and gamma-irradiation demonstrating that PARP is involved in recovery from DNA damage that triggers the Base Excision Repair (BER) process. To address the issue of the role of PARP in BER, the ability of PARP-deficient mammalian cell extracts to Repair a single abasic site present on a circular duplex plasmid molecule was tested in a standard in vitro Repair assay. The results clearly demonstrate, for the first time, the involvement of PARP in the DNA synthesis step of the Base Excision Repair process.
Rajendra Prasad - One of the best experts on this subject based on the ideXlab platform.
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Damage sensor role of UV-DDB during Base Excision Repair
Nature Structural & Molecular Biology, 2019Co-Authors: Sunbok Jang, Namrata Kumar, Emily C. Beckwitt, Muwen Kong, Elise Fouquerel, Vesna Rapić-otrin, Cindy Khuu, Simon C Watkins, Rajendra Prasad, Chandrima MajumdarAbstract:UV-DDB, a key protein in human global nucleotide Excision Repair (NER), binds avidly to abasic sites and 8-oxo-guanine (8-oxoG), suggesting a noncanonical role in Base Excision Repair (BER). We investigated whether UV-DDB can stimulate BER for these two common forms of DNA damage, 8-oxoG and abasic sites, which are Repaired by 8-oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease (APE1), respectively. UV-DDB increased both OGG1 and APE1 strand cleavage and stimulated subsequent DNA polymerase β-gap filling activity by 30-fold. Single-molecule real-time imaging revealed that UV-DDB forms transient complexes with OGG1 or APE1, facilitating their dissociation from DNA. Furthermore, UV-DDB moves to sites of 8-oxoG Repair in cells, and UV-DDB depletion sensitizes cells to oxidative DNA damage. We propose that UV-DDB is a general sensor of DNA damage in both NER and BER pathways, facilitating damage recognition in the context of chromatin.A combination of biochemical, single-molecule, and in vivo assays reveals that the UV-DDB complex that removes UV-induced DNA lesions via the nucleotide Excision Repair pathway also promotes removal of oxidative lesions via Base Excision Repair.
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HMGB1: roles in Base Excision Repair and related function.
Biochimica et Biophysica Acta, 2010Co-Authors: Yuan Liu, Rajendra Prasad, Samuel H. WilsonAbstract:High mobility group box 1 (HMGB1) is a nonhistone architectural protein that is involved in many biological processes including chromatin remodeling, transcription, cell signaling of inflammation, DNA damage Repair and others. Recent studies have identified the cross-link of HMGB1 with a DNA Base Excision Repair intermediate indicating that this protein is involved in Base Excision Repair (BER) pathway. Further characterization of the roles of HMGB1 in BER demonstrates that the protein acts as a cofactor to regulate BER sub-pathways by inhibiting single-nucleotide BER and stimulating long-patch BER through modulating the activities of Base Excision Repair enzymes. Directing of Base lesion Repair to the long-patch sub-pathway can result in trinucleotide repeat instability suggesting an important role of HMGB1 in modulating genome stability.
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requirement of mammalian dna polymerase beta in Base Excision Repair
Nature, 1996Co-Authors: Robert W. Sobol, Rajendra Prasad, Julie K Horton, Ralf Kuhn, Hua Gu, Rakesh K Singhal, Klaus Rajewsky, Samuel H. WilsonAbstract:Synthesis of DNA by DNA polymerase-beta is distributive on single-stranded DNA templates, but short DNA gaps with a 5' PO4 in the gap are filled processively to completion. In vitro studies have suggested a role of beta-polymerase in different types of DNA Repair. However, the significance of these studies to the in vivo role of beta-polymerase has remained unclear. Because genetic studies are essential for determining the physiological role of a gene, we established embryonic fibroblast cell lines homozygous for a deletion mutation in the gene encoding DNA polymerase-beta. Extracts from these cell lines were found to be defective in uracil-initiated Base-Excision Repair. The beta-polymerase-deleted cells are normal in viability and growth characteristics, although they exhibit increased sensitivity to monofunctional DNA-alkylating agents, but not to other DNA-damaging agents. Both the deficiency in Base-Excision Repair and hypersensitivity to DNA-alkylating agents are rescued following stable transfection with a wild-type beta-polymerase minitransgene. These studies demonstrate that beta-polymerase functions specifically in Base-Excision Repair in vivo.
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dna polymerase beta conducts the gap filling step in uracil initiated Base Excision Repair in a bovine testis nuclear extract
Journal of Biological Chemistry, 1995Co-Authors: Rakesh K Singhal, Rajendra Prasad, Samuel H. WilsonAbstract:Abstract The G:U mismatch in genomic DNA mainly arises from deamination of cytosine residues and is Repaired by the Base Excision Repair pathway. We found that a bovine testis crude nuclear extract conducts uracil-initiated Base Excision Repair in vitro. A 51-Base pair synthetic DNA substrate containing a single G:U mismatch was used, and incorporation of dCMP during Repair was exclusively to replace uracil. A neutralizing polyclonal antibody against DNA polymerase β (β-pol) inhibited the Repair reaction. ddCTP also inhibited the Repair reaction, whereas aphidicolin had no significant effect, suggesting that activity of β-pol was required. Next, the Base Excision Repair system was reconstituted using partially purified components. Several of the enzymatic activities required were resolved, such that DNA ligase and the uracil-DNA glycosylase/apurinic/apyrimidinic endonuclease activities were separated from the DNA polymerase requirement. We found that purified β-pol could restore full DNA Repair activity to the DNA polymerase-depleted fraction, whereas purified DNA polymerases α, , and could not. These results with purified proteins corroborated results obtained with the crude extract and indicate that β-pol is responsible for the single-nucleotide gap filling reaction involved in this in vitro Base Excision Repair system.
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dna polymerase β conducts the gap filling step in uracil initiated Base Excision Repair in a bovine testis nuclear extract
Journal of Biological Chemistry, 1995Co-Authors: Rakesh K Singhal, Rajendra Prasad, Samuel H. WilsonAbstract:The G:U mismatch in genomic DNA mainly arises from deamination of cytosine residues and is Repaired by the Base Excision Repair pathway. We found that a bovine testis crude nuclear extract conducts uracil-initiated Base Excision Repair in vitro. A 51-Base pair synthetic DNA substrate containing a single G:U mismatch was used, and incorporation of dCMP during Repair was exclusively to replace uracil. A neutralizing polyclonal antibody against DNA polymerase β (β-pol) inhibited the Repair reaction. ddCTP also inhibited the Repair reaction, whereas aphidicolin had no significant effect, suggesting that activity of β-pol was required. Next, the Base Excision Repair system was reconstituted using partially purified components. Several of the enzymatic activities required were resolved, such that DNA ligase and the uracil-DNA glycosylase/apurinic/apyrimidinic endonuclease activities were separated from the DNA polymerase requirement. We found that purified β-pol could restore full DNA Repair activity to the DNA polymerase-depleted fraction, whereas purified DNA polymerases α, δ , and e could not. These results with purified proteins corroborated results obtained with the crude extract and indicate that β-pol is responsible for the single-nucleotide gap filling reaction involved in this in vitro Base Excision Repair system.
V Schreiber - One of the best experts on this subject based on the ideXlab platform.
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Base Excision Repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1
Biochemistry, 2000Co-Authors: F Dantzer, G De La Rubia, J Ménissier-de Murcia, G Murcia, Z Hostomsky, V SchreiberAbstract:In mammalian cells, damaged Bases in DNA are corrected by the Base Excision Repair pathway which is divided into two distinct pathways depending on the length of the resynthesized patch, replacement of one nucleotide for short-patch Repair, and resynthesis of several nucleotides for long-patch Repair. The involvement of poly(ADP-ribose) polymerase-1 (PARP-1) in both pathways has been investigated by using PARP-1-deficient cell extracts to Repair single abasic sites derived from uracil or 8-oxoguanine located in a double-stranded circular plasmid. For both lesions, PARP-1-deficient cell extracts were about half as efficient as wild-type cells at the polymerization step of the short-patch Repair synthesis, but were highly inefficient at the long-patch Repair. We provided evidence that PARP-1 constitutively interacts with DNA polymerase beta. Using cell-free extracts from mouse embryonic cells deficient in DNA polymerase beta, we demonstrated that DNA polymerase beta is involved in the Repair of uracil-derived AP sites via both the short and the long-patch Repair pathways. When both PARP-1 and DNA polymerase beta were absent, the two Repair pathways were dramatically affected, indicating that Base Excision Repair was highly inefficient. These results show that PARP-1 is an active player in DNA Base Excision Repair.
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Involvement of poly(ADP-ribose) polymerase in Base Excision Repair
Biochimie, 1999Co-Authors: F Dantzer, V Schreiber, C Niedergang, C Trucco, E Flatter, G De La Rubia, J Oliver, V Rolli, J Ménissier-de Murcia, G MurciaAbstract:Poly(ADP-ribose) polymerase (PARP) is a zinc-finger DNA binding protein that detects and signals DNA strand breaks generated directly or indirectly by genotoxic agents. In response to these lesions, the immediate poly(ADP-ribosylation) of nuclear proteins converts DNA interruptions into intracellular signals that activate DNA Repair or cell death programs. To elucidate the biological function of PARP in vivo, the mouse PARP gene was inactivated by homologous recombination to generate mice lacking a functional PARP gene. PARP knockout mice and the derived mouse embryonic fibroblasts (MEFs) were acutely sensitive to monofunctional alkylating agents and gamma-irradiation demonstrating that PARP is involved in recovery from DNA damage that triggers the Base Excision Repair (BER) process. To address the issue of the role of PARP in BER, the ability of PARP-deficient mammalian cell extracts to Repair a single abasic site present on a circular duplex plasmid molecule was tested in a standard in vitro Repair assay. The results clearly demonstrate, for the first time, the involvement of PARP in the DNA synthesis step of the Base Excision Repair process.
Grigory L Dianov - One of the best experts on this subject based on the ideXlab platform.
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Mammalian Base Excision Repair: the Forgotten Archangel
Nucleic acids research, 2013Co-Authors: Grigory L Dianov, Ulrich HübscherAbstract:Base Excision Repair (BER) is a frontline Repair system that is responsible for maintaining genome integrity and thus preventing premature aging, cancer and many other human diseases by Repairing thousands of DNA lesions and strand breaks continuously caused by endogenous and exogenous mutagens. This fundamental and essential function of BER not only necessitates tight control of the continuous availability of basic components for fast and accurate Repair, but also requires temporal and spatial coordination of BER and cell cycle progression to prevent replication of damaged DNA. The major goal of this review is to critically examine controversial and newly emerging questions about mammalian BER pathways, mechanisms regulating BER capacity, BER responses to DNA damage and their links to checkpoint control of DNA replication.
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Base Excision Repair targets for cancer therapy.
American journal of cancer research, 2011Co-Authors: Grigory L DianovAbstract:Cellular DNA Repair is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by Repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments e.g. chemotherapy and ionizing radiation. The major goal of this review is to critically exam the Base Excision Repair pathway and mechanisms regulating Base Excision Repair capacity as a potential targets for improving cancer therapy.
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Review Article Base Excision Repair targets for cancer therapy
2011Co-Authors: Grigory L DianovAbstract:Cellular DNA Repair is a frontline system that is responsible for maintaining genome integrity and thus pre- venting premature aging and cancer by Repairing DNA lesions and strand breaks caused by endogenous and exoge- nous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments e.g. chemotherapy and ionizing radiation. The major goal of this review is to critically exam the Base Excision Repair pathway and mechanisms regulating Base Excision Repair capacity as a potential tar- gets for improving cancer therapy.
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Base Excision Repair fidelity in normal and cancer cells
Mutagenesis, 2006Co-Authors: Katie K.l. Chan, Qiu-mei Zhang, Grigory L DianovAbstract:In mammalian cells, Base Excision Repair (BER) is the major Repair pathway involved in the removal of non-bulky damaged nucleotides. The fidelity of BER is dependent on the polymerization step, where the major BER DNA polymerase (Pol beta) must incorporate the correct Watson-Crick Base paired nucleotide into the one nucleotide Repair gap. Recent studies have indicated that expression of some Pol beta variants or changes in expression of wild-type Pol beta protein, frequently found in cancer cells, can lead to DNA Repair synthesis errors and confers to cells a mutator phenotype.
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exchangeability of mammalian dna ligases between Base Excision Repair pathways
Biochemistry, 2004Co-Authors: Kate M Sleeth, Robert L Robson, Grigory L DianovAbstract:In mammalian cells, DNA ligase IIIα and DNA ligase I participate in the short- and long-patch Base Excision Repair pathways, respectively. Using an in vitro Repair assay employing DNA ligase-deplet...