W R N
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Molecular Mechanisms Of Werner S Syndrome
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Author : Michel Lebel
language : en
Publisher: Springer Science & Business Media
Release Date : 2004-09-14
Molecular Mechanisms Of Werner S Syndrome written by Michel Lebel and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004-09-14 with Medical categories.
During our short time on earth, we all undergo the highly complex process of aging, and with it, we experience the many physiological symptoms. Studies of premature aging have produced a great deal of information that gives some aspects of aging a better understanding. This book explores Werner's syndrome. To some, Werner's syndrome is considered a caricature of aging, but others will find it fascinating that only one mutated human gene (WRN) can bring about a multitude of complicated phenotypes that are usually associated with aging.
Comprehensive Analysis Of Wrn Protein Interaction Network By Mass Spectrometry
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Author : Veronika A. Glukhova
language : en
Publisher:
Release Date : 2014
Comprehensive Analysis Of Wrn Protein Interaction Network By Mass Spectrometry written by Veronika A. Glukhova and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014 with categories.
Cells that have lost WRN function exhibit a shortened replicative lifespan, accumulation of chromosomal aberrations, and demonstrate sensitivity to a number of chemotherapeutic agents, including DNA Topoisomerase I inhibitor camptothecin (CPT). On organismal level, the lack of this protein results in the progeroid syndrome Werner Syndrome, which is characterized by increased incidence of cancers, cardiovascular disease, cataracts, and other age-associated pathologies. In this study we examined the network of proteins that associate with WRN protein, and then expanded this picture when the cells were challenged with CPT. We detail the profiling analysis used for unbiased detection of all interacting proteins using LC-MS/MS, followed by data analysis and selection of targets for follow-up. We then focus on the method development, complexities of data analysis, and application of selected reaction monitoring (SRM), a method for targeted MS. Using RNAi we demonstrate the power of this technique for relative protein quantitation of human proteins WRN and TP53, and a number of small, low-abundance seminal fluid proteins from D.melanogaster flies. SRM was applied for two studies of the WRN interactome: 1) to partially validate findings of the profiling screen after short-term treatment with CPT, and 2) to describe the dynamics of association of these proteins with WRN as a function of time, by expanding the treatment time course to 6 and 12 hours. We report on our description of WRN protein interaction complexes in unperturbed cells, and how these interaction complexes become reorganized in response to DNA damage. Our results demonstrate that the newly recruited proteins participate in chromatin remodeling, negative regulation of cell cycle progression, and double-strand break repair. We focus on 40 proteins to test their differential interaction with WRN after 1, 6, and 12 hours of treatment with CPT. We specifically focus on the functional importance of the chromatin-remodeling factors, and present the list of WRN interacting proteins that have emerged as high-priority targets for functional validation. Finally, we discuss how our work has expanded the understanding of the functional roles of WRN, and how targeted, hypothesis-driven application of mass spectrometry can be used to answer complex questions about protein interaction.
Wrn Exonuclease Structure Molecular Mechanism And Dna Endprocessing Role
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Author :
language : en
Publisher:
Release Date : 2006
Wrn Exonuclease Structure Molecular Mechanism And Dna Endprocessing Role written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006 with categories.
WRN is unique among the five human RecQ DNA helicases by having a functional exonuclease domain (WRN-exo) and being defective in the premature aging and cancer-related disorder Werner syndrome. Here, we characterize WRN-exo crystal structures, biochemical activity and participation in DNA end-joining. Metal ion complex structures, active site mutations and activity assays reveal a two-metal-ion mediated nuclease mechanism. The DNA end-binding Ku70/80 complex specifically stimulates WRN-exo activity, and structure-based mutational inactivation of WRN-exo alters DNA end-joining in human cells. We furthermore establish structural and biochemical similarities of WRN-exo to DnaQ family replicative proofreading exonucleases, with WRN-specific adaptations consistent with dsDNA specificity and functionally important conformational changes. These results indicate WRN-exo is a human DnaQ family member and support analogous proof-reading activities that are stimulated by Ku70/80 with implications for WRN functions in age related pathologies and maintenance of genomic integrity.
The Function Of Mrn Complex During Wrn Facilitated Atm Activation
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Author : Junhao Ma
language : en
Publisher: LAP Lambert Academic Publishing
Release Date : 2010-04
The Function Of Mrn Complex During Wrn Facilitated Atm Activation written by Junhao Ma and has been published by LAP Lambert Academic Publishing this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-04 with categories.
WRN (Werner) protein is a member of the RecQ family showing helicase and exonuclease activity. WRN protein may lose function upon mutation and causes Werner syndrome (WS) which is a cancer-prone and premature aging disease. ATM (Ataxia-Telangiectasia mutated) protein initiates a signaling pathway in response to DNA double strand breaks (DSBs). Genomic disorder ataxia-telangiectasia (A-T) is associated with defective ATM. WRN protein is involved in ATM pathway activation when cells are exposed to DSBs associated with replication fork collapse. Because the Mre11-Rad50-Nbs1 (MRN) complex, a sensor of DSBs, is known to interact with WRN and ATM, we investigated whether the MRN complex mediates the WRN-dependent ATM pathway activation. In this study, we employed short-hairpin RNA to generate WRN- and Nbs1-deficient U-2 OS (osteosarcoma) cells. Cells were treated with clastogens which induce collapsed replication forks, thus provided proof for whether WRN facilitates ATM activation via MRN complex. This study serves as a basis for future investigation on the correlation between ATM, MRN complex and WRN, which will help understand the mechanism of aging and cancer.
Characterizing The Wrn Dna Helicase In Prostate Cancer And Implications For Microsatellite Unstable Metastatic Prostate Cancers
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Author : Emily A. Kohlbrenner
language : en
Publisher:
Release Date : 2021
Characterizing The Wrn Dna Helicase In Prostate Cancer And Implications For Microsatellite Unstable Metastatic Prostate Cancers written by Emily A. Kohlbrenner and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.
Prostate cancer is the most common non-skin malignancy in men worldwide and the second most common cause of cancer mortality in men. Metastatic prostate cancer (mPC) is highly heterogenous and enriched for aberrations in genes involved in DNA repair, the loss of which generates further genetic alterations and genomic instability that ultimately promotes tumorigenesis. The DNA Helicase-Exonuclease RECQL2 protein, commonly referred to as WRN, plays an integral role in DNA repair by regulating the dynamics of the replication fork. WRN is lost along the 8p chromosomal arm in 10% of prostate cancers; however, the role of WRN in mPC remains unclear. WRN has also been established as a promising target for synthetic lethality in mismatch repair deficient (MMRd) cancer cells with microsatellite instability (MSI), an aggressive subtype of metastatic disease that promotes oncogenesis via genome hypermutability. We aimed to identify the prognostic value of WRN-specific copy loss in mPC patient tumors as well as investigate the sensitivity of MSI-mPC cell models to engineered WRN knockdown. We first showed that adverse outcomes are associated with WRN copy number status in mPC, and connect mutual exclusivity between loss of WRN and mismatch repair deficient tumors using large scale clinical datasets. Then, we tested the sensitivity to WRN inhibitor NSC 19630 in the LUCaP PDX xenograft lines, and found marked sensitivity in tumor lines with DNA Repair Deficiency (DRD). Further, we demonstrated that MSI prostate cancer cells are indeed sensitive to WRN loss over time. Finally, using quantified confocal imaging, we showed that tertiary DNA secondary structures at GC rich regions, known as G-Quadruplexes, are associated with replicative stress in MMRd-MSI cells and are themselves a promising target for chemotherapeutics. Together, this work expands the knowledge of DRD heterogeneity in mPC and provides novel insight into the molecular mechanisms of WRN sensitivity in MSI cells.
Dna Repair And Human Disease
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Author : Adayabalam Balajee
language : en
Publisher: Springer Science & Business Media
Release Date : 2007-03-06
Dna Repair And Human Disease written by Adayabalam Balajee and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007-03-06 with Medical categories.
DNA Repair and Human Disease highlights the molecular complexities of a few well-known human hereditary disorders that arise due to perturbations in the fidelity of diverse DNA repair machineries.
Molecular Oncology
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Author : Frank Joseph Rauscher (III)
language : en
Publisher: Cambridge University Press
Release Date : 2014
Molecular Oncology written by Frank Joseph Rauscher (III) and has been published by Cambridge University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014 with Medical categories.
Reviews the origins of molecular oncology, including technologies for cancer analysis, key pathways in human malignancies, and available pharmacologic therapies.
Nonenzymatic Role For Wrn In Preserving Nascent Dna Strands After Replication Stress
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Author :
language : en
Publisher:
Release Date : 2014
Nonenzymatic Role For Wrn In Preserving Nascent Dna Strands After Replication Stress written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014 with categories.
WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a nonenzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Furthermore, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, this previously unrecognized nonenzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals.
Role Of Wrn Helicase In Repair Of Chromate Induced Dna Damage
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Author : Alma Zecevic
language : en
Publisher:
Release Date : 2008
Role Of Wrn Helicase In Repair Of Chromate Induced Dna Damage written by Alma Zecevic and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with Chromium categories.
Chromium(VI) produces a complex array of DNA-adducts and lesions. Processing of DNA-chromium adducts by mismatch repair produced double strand breaks that are the main source of cellular death. Werner syndrome protein is a RecQ helicase and is suspected that it plays a role in homologous recombination. However, definitive proof of WRN activity in repair of DNA double strand breaks has thus far been missing. We show that WRN deficiency predisposes cells to chromium(VI) sensitivity. We also show that cells lacking WRN retain double strand breaks longer than their isogenic control and that this retention corresponds with a lack of RAD51 foci formation. A result of WRN deficiency in chromium(VI) exposure results in mitotic arrest as illustrated by elevated populations of cells in M phase. Considering that mismatch repair has been shown to be responsible for formation of double strand breaks after chromium(VI) exposure, we looked at the effects of mismatch repair on WRN protein dynamics and deficiency. WRN protein delocalization from the nucleolus depends on the presence of mismatch repair proteins and a double deficiency in both WRN and MMR renders cells with no discernable defect in mitotic progression or repair of double strand breaks. Our results suggest that WRN is necessary for prompt activation of homologous recombination for repair of mismatch repair mediated double strand breaks after chromium(VI) exposure.
Molecular Themes In Dna Replication
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Author : Lynne S Cox
language : en
Publisher: Royal Society of Chemistry
Release Date : 2009-10-31
Molecular Themes In Dna Replication written by Lynne S Cox and has been published by Royal Society of Chemistry this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-10-31 with Science categories.
DNA replication, the process of copying one double stranded DNA molecule to form two identical copies, is highly conserved at the mechanistic level across evolution. Interesting in its own right as a fascinating feat of biochemical regulation and coordination, DNA replication is at the heart of modern advances in molecular biology. An understanding of the process at both the biological and chemical level is essential to developing new techniques in molecular biology. Insights into the process at the molecular level provide opportunities to modulate and intervene in replication. Rapidly dividing cells need to replicate their DNA prior to division, and targeting components of the replication process is a potentially powerful strategy in cancer treatment. Conversely, ageing may be associated with loss of replication activity and restoring it to cells may moderate some of the diseases associated with old age. Replication is, therefore, fundamental to a huge range of molecular biological and biochemical applications, and provides many potential targets for drug design. The fast pace of replication research, particularly in providing new structural insights, has outdated the majority of available texts. This learned, yet accessible, book contains the latest research written by those conducting it. It examines conserved themes providing a biological background for biochemical, chemical and pharmaceutical studies of this huge and exciting field. Rather than simply "itemising" the replication steps and the proteins involved, replication is tackled from a novel perspective. The book provides logical groupings of processes based upon biochemical similarities. The emphasis on mechanisms and the relationship between structure and function targets the chapters towards biochemists and biological chemists as well as molecular and cell biologists. The book highlights new insights into the replication process, from the assembly of pre-replication complexes, through polymerisation mechanisms, to considering replication in the context of chromatin and chromosomes. It also covers mitochondrial DNA replication, and includes archaeal paradigms, which are proving increasingly relevant to the study of replication in higher eukaryotes. Exciting potential drug targets in DNA replication are discussed, particularly in the context of treating malaria and cancer.