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Author: Publisher: ISBN: Category : Languages : en Pages :
Book Description
The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair by recognizing DNA lesions before recruiting downstream factors. How XPC detects structurally diverse lesions embedded within normal DNA is unknown. Here we present a crystal structure that captures the yeast XPC orthologue (Rad4) on a single register of undamaged DNA. The structure shows that a disulphide-tethered Rad4 flips out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Contrary to many DNA repair enzymes that can directly reject non-target sites as structural misfits, our results suggest that Rad4/XPC uses a kinetic gating mechanism whereby lesion selectivity arises from the kinetic competition between DNA opening and the residence time of Rad4/XPC per site. This mechanism is further supported by measurements of Rad4-induced lesion-opening times using temperature-jump perturbation spectroscopy. Lastly, kinetic gating may be a general mechanism used by site-specific DNA-binding proteins to minimize time-consuming interrogations of non-target sites.
Author: Publisher: ISBN: Category : Languages : en Pages :
Book Description
The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair by recognizing DNA lesions before recruiting downstream factors. How XPC detects structurally diverse lesions embedded within normal DNA is unknown. Here we present a crystal structure that captures the yeast XPC orthologue (Rad4) on a single register of undamaged DNA. The structure shows that a disulphide-tethered Rad4 flips out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Contrary to many DNA repair enzymes that can directly reject non-target sites as structural misfits, our results suggest that Rad4/XPC uses a kinetic gating mechanism whereby lesion selectivity arises from the kinetic competition between DNA opening and the residence time of Rad4/XPC per site. This mechanism is further supported by measurements of Rad4-induced lesion-opening times using temperature-jump perturbation spectroscopy. Lastly, kinetic gating may be a general mechanism used by site-specific DNA-binding proteins to minimize time-consuming interrogations of non-target sites.
Author: Yogambigai Velmurugu Publisher: Springer ISBN: 3319451294 Category : Science Languages : en Pages : 218
Book Description
Using a novel approach that combines high temporal resolution of the laser T-jump technique with unique sets of fluorescent probes, this study unveils previously unresolved DNA dynamics during search and recognition by an architectural DNA bending protein and two DNA damage recognition proteins. Many cellular processes involve special proteins that bind to specific DNA sites with high affinity. How these proteins recognize their sites while rapidly searching amidst ~3 billion nonspecific sites in genomic DNA remains an outstanding puzzle. Structural studies show that proteins severely deform DNA at specific sites and indicate that DNA deformability is a key factor in site-specific recognition. However, the dynamics of DNA deformations have been difficult to capture, thus obscuring our understanding of recognition mechanisms. The experiments presented in this thesis uncover, for the first time, rapid (~100-500 microseconds) DNA unwinding/bending attributed to nonspecific interrogation, prior to slower (~5-50 milliseconds) DNA kinking/bending/nucleotide-flipping during recognition. These results help illuminate how a searching protein interrogates DNA deformability and eventually “stumbles” upon its target site. Submillisecond interrogation may promote preferential stalling of the rapidly scanning protein at cognate sites, thus enabling site-recognition. Such multi-step search-interrogation-recognition processes through dynamic conformational changes may well be common to the recognition mechanisms for diverse DNA-binding proteins.
Author: Wolfram Siede Publisher: CRC Press ISBN: 0849352681 Category : Medical Languages : en Pages : 871
Book Description
Stands as the most comprehensive guide to the subject-covering every essential topic related to DNA damage identification and repair. Covering a wide array of topics from bacteria to human cells, this book summarizes recent developments in DNA damage repair and recognition while providing timely reviews on the molecular mechanisms employe
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: 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: Chikako Nishigori Publisher: Springer ISBN: 9811067228 Category : Medical Languages : en Pages : 221
Book Description
This book focuses on the clinical aspects of DNA repair disorders. Nucleotide excision repair is an important pathway for humans, as it is involved in biologically fundamental functions. This work presents clinical features together with the pathogenesis of DNA repair disorders such as Xertoderma Pigmentosum (XP). Studies on animal models are included as well. Clinical feature characteristics of each clinical subtype of XP are depicted according to the genotype, giving accurate and detailed information about the clinical features in terms of gene alterations, change of protein structure, and dysfunction in some of the repair pathways. This book is unique in that it provides detailed information on clinical features from more than 100 patients with XP-A, which is characterized by very severe manifestation of skin photosensitivity and neurological dysfunction. It will give readers important knowledge for understanding the concept and molecular mechanisms of DNA repair disorders. It also describes how to treat and care for patients with XP based on vast experience in clinical practice. DNA Repair Disorders will be a useful resource not only for physicians and basic scientists who are interested in and/or take care of patients with DNA repair disorders, but also dermatologists, neurologists, and researchers in the field of radiation biology and photobiology.
Author: Phoebe A. Rice Publisher: Royal Society of Chemistry ISBN: 0854042725 Category : Science Languages : en Pages : 417
Book Description
This book provides both in-depth background and up-to-date information in this area. The chapters are organized by general themes and principles, written by experts who illustrate topics with current findings. Topics covered include: - the role of ions and hydration in protein-nucleic acid interactions - transcription factors and combinatorial specificity - indirect readout of DNA sequence - single-stranded nucleic acid binding proteins - nucleic acid junctions and proteins, - RNA protein recognition - recognition of DNA damage. It will be a key reference for both advanced students and established scientists wishing to broaden their horizons.
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Author: 
Author: Yogambigai Velmurugu
Author: Wolfram Siede
Author: Hanspeter Naegeli
Author: Flurina Christina Clement Frey
Author: Muwen Kong
Author: Archana Schrestha
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Author: Chikako Nishigori
Author: Phoebe A. Rice