scholarly journals A Mathematical Model for DNA Damage and Repair

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Philip S. Crooke ◽  
Fritz F. Parl
Keyword(s):  
Mathematical Model ◽  
Dna Damage ◽  
Dna Adducts ◽  
Excision Repair ◽  
Estrogen Metabolism ◽  
Enzymatic Reactions ◽  
Dna Damage And Repair ◽  
Base Excision ◽  
The Impact ◽  
Variant Enzyme

In cells, DNA repair has to keep up with DNA damage to maintain the integrity of the genome and prevent mutagenesis and carcinogenesis. While the importance of both DNA damage and repair is clear, the impact of imbalances between both processes has not been studied. In this paper, we created a combined mathematical model for the formation of DNA adducts from oxidative estrogen metabolism followed by base excision repair (BER) of these adducts. The model encompasses a set of differential equations representing the sequence of enzymatic reactions in both damage and repair pathways. By combining both pathways, we can simulate the overall process by starting from a given time-dependent concentration of 17β-estradiol (E2) and2′-deoxyguanosine, determine the extent of adduct formation and the correction by BER required to preserve the integrity of DNA. The model allows us to examine the effect of phenotypic and genotypic factors such as different concentrations of estrogen and variant enzyme haplotypes on the formation and repair of DNA adducts.

scholarly journals Mechanistic Insight into DNA Damage and Repair in Ischemic Stroke: Exploiting the Base Excision Repair Pathway as a Model of Neuroprotection

2011 ◽  
Vol 14 (10) ◽  
pp. 1905-1918 ◽  
Author(s):  
Peiying Li ◽  
Xiaoming Hu ◽  
Yu Gan ◽  
Yanqin Gao ◽  
Weimin Liang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ischemic Stroke ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Dna Damage And Repair ◽  
Base Excision Repair Pathway ◽  
Mechanistic Insight ◽  
Base Excision ◽  
Insight Into

scholarly journals Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

2005 ◽  
Vol 25 (14) ◽  
pp. 5823-5833 ◽  
Author(s):  
Yingying Guo ◽  
Linda L. Breeden ◽  
Helmut Zarbl ◽  
Bradley D. Preston ◽  
David L. Eaton
Keyword(s):  
Dna Damage ◽  
Cytochrome P450 ◽  
Nucleotide Excision Repair ◽  
Dna Adducts ◽  
Excision Repair ◽  
Cell Cycle Checkpoints ◽  
Postreplication Repair ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Aflatoxin B

ABSTRACT Aflatoxin B1 (AFB1) is a human hepatotoxin and hepatocarcinogen produced by the mold Aspergillus flavus. In humans, AFB1 is primarily bioactivated by cytochrome P450 1A2 (CYP1A2) and 3A4 to a genotoxic epoxide that forms N7-guanine DNA adducts. A series of yeast haploid mutants defective in DNA repair and cell cycle checkpoints were transformed with human CYP1A2 to investigate how these DNA adducts are repaired. Cell survival and mutagenesis following aflatoxin B1 treatment was assayed in strains defective in nucleotide excision repair (NER) (rad14), postreplication repair (PRR) (rad6, rad18, mms2, and rad5), homologous recombinational repair (HRR) (rad51 and rad54), base excision repair (BER) (apn1 apn2), nonhomologous end-joining (NHEJ) (yku70), mismatch repair (MMR) (pms1), translesion synthesis (TLS) (rev3), and checkpoints (mec1-1, mec1-1 rad53, rad9, and rad17). Together our data suggest the involvement of homologous recombination and nucleotide excision repair, postreplication repair, and checkpoints in the repair and/or tolerance of AFB1-induced DNA damage in the yeast model. Rev3 appears to mediate AFB1-induced mutagenesis when error-free pathways are compromised. The results further suggest unique roles for Rad5 and abasic endonuclease-dependent DNA intermediates in regulating AFB1-induced mutagenicity.

scholarly journals Genetic Analysis of Transcription-Associated Mutation in Saccharomyces cerevisiae

Genetics ◽  
2000 ◽  
Vol 154 (1) ◽  
pp. 109-120 ◽  
Author(s):  
Natalie J Morey ◽  
Christopher N Greene ◽  
Sue Jinks-Robertson
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Mutation Rates ◽  
Base Pairs ◽  
Genetic Studies ◽  
Dna Damage And Repair ◽  
Nucleotide Excision ◽  
Translesion Bypass ◽  
Base Excision

Abstract High levels of transcription are associated with elevated mutation rates in yeast, a phenomenon referred to as transcription-associated mutation (TAM). The transcription-associated increase in mutation rates was previously shown to be partially dependent on the Rev3p translesion bypass pathway, thus implicating DNA damage in TAM. In this study, we use reversion of a pGAL-driven lys2ΔBgl allele to further examine the genetic requirements of TAM. We find that TAM is increased by disruption of the nucleotide excision repair or recombination pathways. In contrast, elimination of base excision repair components has only modest effects on TAM. In addition to the genetic studies, the lys2ΔBgl reversion spectra of repair-proficient low and high transcription strains were obtained. In the low transcription spectrum, most of the frameshift events correspond to deletions of AT base pairs whereas in the high transcription strain, deletions of GC base pairs predominate. These results are discussed in terms of transcription and its role in DNA damage and repair.

Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets

2020 ◽  
Vol 27 (12) ◽  
pp. 1901-1921 ◽  
Author(s):  
Aleksandra Rajapakse ◽  
Amila Suraweera ◽  
Didier Boucher ◽  
Ali Naqi ◽  
Kenneth O'Byrne ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Redox Regulation ◽  
Therapeutic Potential ◽  
Excision Repair ◽  
Cellular Transformation ◽  
Enzymatic Reactions ◽  
Base Damage ◽  
Base Excision

Background:Reactive Oxygen Species (ROS) are by-products of normal cellular metabolic processes, such as mitochondrial oxidative phosphorylation. While low levels of ROS are important signalling molecules, high levels of ROS can damage proteins, lipids and DNA. Indeed, oxidative DNA damage is the most frequent type of damage in the mammalian genome and is linked to human pathologies such as cancer and neurodegenerative disorders. Although oxidative DNA damage is cleared predominantly through the Base Excision Repair (BER) pathway, recent evidence suggests that additional pathways such as Nucleotide Excision Repair (NER) and Mismatch Repair (MMR) can also participate in clearance of these lesions. One of the most common forms of oxidative DNA damage is the base damage 8-oxoguanine (8-oxoG), which if left unrepaired may result in G:C to A:T transversions during replication, a common mutagenic feature that can lead to cellular transformation.Objective:Repair of oxidative DNA damage, including 8-oxoG base damage, involves the functional interplay between a number of proteins in a series of enzymatic reactions. This review describes the role and the redox regulation of key proteins involved in the initial stages of BER of 8-oxoG damage, namely Apurinic/Apyrimidinic Endonuclease 1 (APE1), human 8-oxoguanine DNA glycosylase-1 (hOGG1) and human single-stranded DNA binding protein 1 (hSSB1). Moreover, the therapeutic potential and modalities of targeting these key proteins in cancer are discussed.Conclusion:It is becoming increasingly apparent that some DNA repair proteins function in multiple repair pathways. Inhibiting these factors would provide attractive strategies for the development of more effective cancer therapies.

Ischemic Neuronal Apoptosis: A View Based on Free Radical-Induced DNA Damage and Repair

1998 ◽  
Vol 4 (2) ◽  
pp. 88-95 ◽  
Author(s):  
Arif Y. Shaikh ◽  
Uthayshanker R. Ezekiel ◽  
Philip K. Liu ◽  
Chung Y. Hsu
Keyword(s):  
Dna Damage ◽  
Free Radicals ◽  
Free Radical ◽  
Base Excision Repair ◽  
Neuronal Apoptosis ◽  
Excision Repair ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Dna Damage And Repair ◽  
Base Excision

Neurons are different from other cells in that they are postmitotic and not replaced after they are lost. The CNS is thus particularly vulnerable to neuronal cell loss from various causes, including ischemic injury. Recent observations show that apoptosis is a common feature in neurons dying of ischemic injury. Free radicals have been implicated in the pathogenesis of ischemic brain injury. Reperfusion after cerebral ischemia is accompanied by excessive free radical formation. Many of these free radicals are reactive oxygen species and cause oxidative damage to DNA. The base-excision repair pathway is believed to repair oxidative DNA damage in the brain after ischemia-reperfusion. We review recent laboratory findings that provide evidence of free radical-induced DNA damage and repair after ischemic injury. The polymerase responsible for replication during base-excision repair, DNA polymerase-β, lacks proofreading activity and is considered error prone. This may lead to the accumulation of DNA damage and genomic instability, probable causes of accelerated neuronal aging. A number of DNA repair genes, including ataxia teleangiectasia, p53, and poly(ADP-ribose) polymerase, are activated after DNA damage. The pathogenetic roles of these genes in ischemia-induced neuronal apoptosis are under active investigation. NEUROSCIENTIST 4:88-95, 1998

Corrigendum to “DNA damage response protein ASCIZ links base excision repair with immunoglobulin gene conversion” [Biochem. Biophys. Res. Commun. 371 (2008) 225–229]

2008 ◽  
Vol 377 (1) ◽  
pp. 326
Author(s):  
Hayato Oka ◽  
Wataru Sakai ◽  
Eiichiro Sonoda ◽  
Jun Nakamura ◽  
Kenjiro Asagoshi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Conversion ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Immunoglobulin Gene ◽  
Damage Response ◽  
Base Excision

scholarly journals Evolving Role of Genomics in Genitourinary Neoplasms

2019 ◽  
Vol 48 (1) ◽  
pp. 68
Author(s):  
Michael E. Devitt ◽  
Robert Dreicer
Keyword(s):  
Dna Damage ◽  
Genomic Data ◽  
Treatment Decisions ◽  
Response To Therapy ◽  
Genomic Alterations ◽  
Dna Damage And Repair ◽  
Genitourinary Cancer ◽  
Genitourinary Cancers ◽  
The Impact

<p>The aim of this article is to review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies. The authors selected guidelines, publications, and abstracts relevant to the current and emerging role of genomics in genitourinary cancers. The risk of developing genitourinary cancer can be stratified based on genomic data. Prostate cancer has the strongest degree of heritability, with <em>BRCA1/2 </em>and <em>HOXB13 </em>mutations playing a role in familial disease. Genomic data is on the verge of informing treatment decisions across genitourinary cancers. mCRPC has diverse genomic alterations that represent potential therapeutic targets, including alterations in the AR pathway, DNA damage and repair pathways, cell cycle pathways, PI3K pathway, and Wnt signaling. Genomic alterations in clear cell renal cell carcinoma can inform prognosis and mutations in mTOR pathways predict response to mTOR inhibitors. Urothelial carcinoma can be classified into different subtypes based on gene expression profiling, which provides prognostic information and predicts response to chemotherapy and immunotherapy. Specific mutations have been identified that predict response to therapy including <em>ERCC2 </em>mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and <em>FGFR3 </em>mutations and FGFR tyrosine kinase inhibitors such as erdafitinib.</p><p><strong>Conclusion. </strong>Genitourinary malignancies have not felt the impact of genomic data as greatly as other cancer types. The majority of benefit lies in identifying patients at high risk of genitourinary cancer. Fortunately, breakthroughs are on the horizon that will result in a greater incorporation of genomic information into treatment decisions for patients with genitourinary cancer.</p>

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