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Author: Archana Schrestha Publisher: ISBN: Category : Xeroderma pigmentosum Languages : en Pages : 138
Book Description
Nucleotide Excision Repair (NER) is a major DNA repair mechanism after UV light exposure. Rad23 in combination with Rad4, Nucleotide Excision Repair Factor 2 (NEF2), play a critical role in DNA damage recognition. Mutation or loss of the RAD4 human homolog, XPC, can lead to a serious disorder, Xeroderma Pigmentosum, which is characterized by increased sensitivity to sunlight and predisposition to cancer. Little is known about how Rad23 can function in both these roles and what signals are needed to stabilize a protein verses send it to the proteasome for degradation. Current research in Dr. Smith's lab has shown that the ubiquitin like (UBL) domain of Rad23 is often found to be ubiquitinated after UV light exposure which coincides with the increased level of Rad4. The objective of this project is to determine if the ubiquitination on Rad23 is involved in Rad4 stabilization in yeast, Saccharomyces. In order to determine the site of UV-dependent ubiquitin modification within the UBL domain of Rad23, 14 lysine residues were replaced by arginine individually as well as in various combinations. Molecular techniques such as UV sensitivity assays and western blots were applied to study the functional properties of these Rad23 mutants in Saccharomyces, and the role of ubiquitination following UV exposure. The site directed mutagenesis performed in this study has reiterated the importance of UBL domain since the combination mutants (lysine substituted by arginine) were UV sensitive.
Author: Archana Schrestha Publisher: ISBN: Category : Xeroderma pigmentosum Languages : en Pages : 138
Book Description
Nucleotide Excision Repair (NER) is a major DNA repair mechanism after UV light exposure. Rad23 in combination with Rad4, Nucleotide Excision Repair Factor 2 (NEF2), play a critical role in DNA damage recognition. Mutation or loss of the RAD4 human homolog, XPC, can lead to a serious disorder, Xeroderma Pigmentosum, which is characterized by increased sensitivity to sunlight and predisposition to cancer. Little is known about how Rad23 can function in both these roles and what signals are needed to stabilize a protein verses send it to the proteasome for degradation. Current research in Dr. Smith's lab has shown that the ubiquitin like (UBL) domain of Rad23 is often found to be ubiquitinated after UV light exposure which coincides with the increased level of Rad4. The objective of this project is to determine if the ubiquitination on Rad23 is involved in Rad4 stabilization in yeast, Saccharomyces. In order to determine the site of UV-dependent ubiquitin modification within the UBL domain of Rad23, 14 lysine residues were replaced by arginine individually as well as in various combinations. Molecular techniques such as UV sensitivity assays and western blots were applied to study the functional properties of these Rad23 mutants in Saccharomyces, and the role of ubiquitination following UV exposure. The site directed mutagenesis performed in this study has reiterated the importance of UBL domain since the combination mutants (lysine substituted by arginine) were UV sensitive.
Author: Kristijan Ramadan Publisher: Frontiers Media SA ISBN: 288945441X Category : Languages : en Pages : 183
Book Description
DNA damage response (DDR) is a term that includes a variety of highly sophisticated mechanisms that cells have evolved in safeguarding the genome from the deleterious consequences of DNA damage. It is estimated that every single cell receives tens of thousands of DNA lesions per day. Failure of DDR to properly respond to DNA damage leads to stem cell dysfunction, accelerated ageing, various degenerative diseases or cancer. The sole function of DDR is to recognize diverse DNA lesions, signal their presence, activate cell cycle arrest and finally recruit specific DNA repair proteins to fix the DNA damage and thus prevent genomic instability. DDR is composed of hundreds of spatiotemporally regulated and interconnected proteins, which are able to promptly respond to various DNA lesions. So it is not surprising that mutations in genes encoding various DDR proteins cause embryonic lethality, malignancies, neurodegenerative diseases and premature ageing. The importance of DDR for cell survival and genome stability is unquestionable, but how the sophisticated network of hundreds of different DDR proteins is spatiotemporally coordinated is far from being understood. In the last ten years ubiquitin (ubiquitination) and the ubiquitin-relative SUMO (sumoylation) have emerged as essential posttranslational modifications that regulate DDR. Beside a plethora of ubiqutin and sumo E1-activating enzymes, E2-conjugating enzymes, E3-ligases and ubiquitin/sumo proteases involved in ubiquitination and sumoylation, the complexity of ubiqutin and sumo systems is additionally increased by the fact that both ubiquitin and sumo can form a variety of different chains on substrates which govern the substrate fate, such as its interaction with other proteins, changing its enzymatic activity or promoting substrate degradation. The importance of ubiquitin/SUMO systems in the orchestration of DDR is best illustrated in patients with mutations in E3-ubiquitin ligases BRCA1 or RNF168. BRCA1 is essential for proper function of DDR and its mutations lead to triple-negative breast and ovarian cancers. RNF168 is an E3 ubiquitin ligase, which creates the ubiquitin docking platform for recruitment of different DNA damage signalling and repair proteins at sites of DNA lesion, and its mutations cause RIDDLE syndrome characterized by radiosensitivity, immunodeficiency and learning disability. In addition, recently discovered the ubiquitin receptor protein SPRTN is part of the DNA replication machinery and its mutations cause early-onset hepatocellular carcinoma and premature ageing in humans. Despite more than 700 different enzymes directly involved in ubiquitination and sumoylation processes only few of them are known to play a role in DDR. Therefore, we feel that the role of ubiquitin and the ubiquitin-related SUMO in DDR is far from being understood, and that this is the emerging field that will hugely expand in the next decade due to the rapid development of a new generation of technologies, which will allow us a more robust and precise analyses of human genome, transcriptome and proteome. In this Research Topic we provide a comprehensive overview of our current understanding of ubiquitin and SUMO pathways in all aspects of DDR, from DNA replication to different DNA repair pathways, and demonstrate how alterations in these pathways cause genomic instability that is linked to degenerative diseases, cancer and pathological ageing.
Author: Effrossyni Boutou Publisher: BoD – Books on Demand ISBN: 1789235847 Category : Science Languages : en Pages : 221
Book Description
DNA damage response (DDR) and lesion repair are vital processes ensuring genome integrity through various pathways depending mainly on the nature of DNA injury and cell cycle stage. DDR is finely regulated at many levels in co-ordination with other ongoing processes as is genome replication and cell cycle progression. Posttranslational modifications (PTMs), affecting both protein-protein and protein-DNA interactions, play a crucial role in finely tuning all processes involved in the restoration of genome lesions. Regarding damaged chromatin, PTMs serve in many cases as recruitment platforms for DNA repair mechanisms by facilitating binding sites or regulating interactions between involved proteins. Ubiquitination, the addition of ubiquitin moieties on a target protein, apart from controlling protein availability through degradation, is also involved, together with partner small ubiquitin-like modifier (SUMO), in controlling many pathways involved in DDR by modifying the structure-function relationship and thus interacting with partner molecules. The aim of this book is to cover a broad spectrum of current topics in ubiquitination and to a lesser extent SUMOylation involvement in regulation of DDR and repair in health and disease. This book is intended for pre- and postgraduate students and young scientists in this field. Members of both academic and research institutions, actively involved in the field, have described their current understanding of major mechanisms involved, highlighted key events, described ongoing applications in both developmental diseases and cancer and provided hints for future potential applications.
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
DNA damage response (DDR) is a term that includes a variety of highly sophisticated mechanisms that cells have evolved in safeguarding the genome from the deleterious consequences of DNA damage. It is estimated that every single cell receives tens of thousands of DNA lesions per day. Failure of DDR to properly respond to DNA damage leads to stem cell dysfunction, accelerated ageing, various degenerative diseases or cancer. The sole function of DDR is to recognize diverse DNA lesions, signal their presence, activate cell cycle arrest and finally recruit specific DNA repair proteins to fix the DNA damage and thus prevent genomic instability. DDR is composed of hundreds of spatiotemporally regulated and interconnected proteins, which are able to promptly respond to various DNA lesions. So it is not surprising that mutations in genes encoding various DDR proteins cause embryonic lethality, malignancies, neurodegenerative diseases and premature ageing. The importance of DDR for cell survival and genome stability is unquestionable, but how the sophisticated network of hundreds of different DDR proteins is spatiotemporally coordinated is far from being understood. In the last ten years ubiquitin (ubiquitination) and the ubiquitin-relative SUMO (sumoylation) have emerged as essential posttranslational modifications that regulate DDR. Beside a plethora of ubiqutin and sumo E1-activating enzymes, E2-conjugating enzymes, E3-ligases and ubiquitin/sumo proteases involved in ubiquitination and sumoylation, the complexity of ubiqutin and sumo systems is additionally increased by the fact that both ubiquitin and sumo can form a variety of different chains on substrates which govern the substrate fate, such as its interaction with other proteins, changing its enzymatic activity or promoting substrate degradation. The importance of ubiquitin/SUMO systems in the orchestration of DDR is best illustrated in patients with mutations in E3-ubiquitin ligases BRCA1 or RNF168. BRCA1 is essential for proper function of DDR and its mutations lead to triple-negative breast and ovarian cancers. RNF168 is an E3 ubiquitin ligase, which creates the ubiquitin docking platform for recruitment of different DNA damage signalling and repair proteins at sites of DNA lesion, and its mutations cause RIDDLE syndrome characterized by radiosensitivity, immunodeficiency and learning disability. In addition, recently discovered the ubiquitin receptor protein SPRTN is part of the DNA replication machinery and its mutations cause early-onset hepatocellular carcinoma and premature ageing in humans. Despite more than 700 different enzymes directly involved in ubiquitination and sumoylation processes only few of them are known to play a role in DDR. Therefore, we feel that the role of ubiquitin and the ubiquitin-related SUMO in DDR is far from being understood, and that this is the emerging field that will hugely expand in the next decade due to the rapid development of a new generation of technologies, which will allow us a more robust and precise analyses of human genome, transcriptome and proteome. In this Research Topic we provide a comprehensive overview of our current understanding of ubiquitin and SUMO pathways in all aspects of DDR, from DNA replication to different DNA repair pathways, and demonstrate how alterations in these pathways cause genomic instability that is linked to degenerative diseases, cancer and pathological ageing.
Author: Publisher: Academic Press ISBN: 0128173971 Category : Science Languages : en Pages : 354
Book Description
DNA Repair, Volume 45 in The Enzymes series highlights new advances in the field, with this new volume presenting interesting chapters on DNA polymerase beta and other gap-filling enzymes in mammalian base excision repair, Translesion polymerases, mechanism and function, The Rev1-Pol? Mutasome: Structure and Interactions in Translesion Synthesis, Challenges for base excision repair enzymes: acquiring access to damaged DNA in chromatin Nucleotide excision repair, DNA damage recognition mechanisms in mammalian nucleotide excision repair, Advances in understanding DNA mismatch repair, and more. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in The Enzymes series
Author: Publisher: ISBN: Category : Biochemistry Languages : en Pages : 532
Book Description
No. 2, pt. 2 of November issue each year from v. 19 (1963)-47 (1970) and v. 55 (1972)- contain the Abstracts of papers presented at the Annual Meeting of the American Society for Cell Biology, 3d (1963)-10th (1970) and 12th (1972)-
Author: Antonio Porro Publisher: Frontiers Media SA ISBN: 2889450570 Category : Languages : en Pages : 308
Book Description
DNA damage is a major threat to genomic integrity and cell survival. It can arise both spontaneously and in response to exogenous agents. DNA damage can attack most parts of the DNA structure, ranging from minor and major chemical modifications, to single-strand breaks (SSBs) and gaps, to full double-strand breaks (DSBs). If DNA injuries are mis-repaired or unrepaired, they may ultimately result in mutations or wider-scale genome aberrations that threaten cell homeostasis. Consequently, the cells elicit an elaborate signalling network, known as DNA damage response (DDR), to detect and repair these cytotoxic lesions. This Research Topic was aimed at comprehensive investigations of basic and novel mechanisms that underlie the DNA damage response in eukaryotes.
Author: Peter Zwickl Publisher: Springer Science & Business Media ISBN: 364259414X Category : Science Languages : en Pages : 222
Book Description
This volume gives an overview of pro tea some-mediated protein degradation and the regulatory role of the ubiquitin system in cellular proteolysis. The first chapter describes the molecular evolution of the proteasome and its associated activators, i. e. , the 20S core, the base and the lid of the 19S cap, and the 11 S regulator. The ensuing chapter gives an overview of the structure and assembly of the 20S proteasome and the regulation of the archaeal proteasome by PAN. The third contribution summarizes our knowledge on the eukaryotic 26S proteasome and its regulation by the 19S regu lator, followed by a chapter devoted to the llS regulator, which elucidates the structural basis for the 11 S-mediated activation of the 20S proteasome. The fifth chapter reviews in detail the role of the proteasome in the immune response. The subsequent chapter of the natural substrates of the gives a comprehensive description proteasome and their recognition by the enzymes of the ubiqui tination machinery. The penultimate chapter rounds up the in formation on intracellular distribution of proteasomes in yeast and mammalian cells, while the last contribution highlights proteasome inhibitors, tools which proved to be very valuable for dissecting the cellular roles of the proteasome and which might turn out to be of pharmacological importance.
Author: Archana Schrestha
Author: Archana Schrestha
Author: Tatiana Grohmann Ortolan
Author: Kristijan Ramadan
Author: Effrossyni Boutou
Author: Warren B. Potts
Author: 
Author: 
Author: 
Author: Antonio Porro
Author: Peter Zwickl