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Results: 1 to 10 of 194

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A key interaction with RPA orients XPA in NER complexes.
Topolska-Woś AM, Sugitani N, Cordoba JJ, Le Meur KV, Le Meur RA, Kim HS, Yeo JE, Rosenberg D, Hammel M, Schärer OD, Chazin WJ
(2020) Nucleic Acids Res 48: 2173-2188
MeSH Terms: DNA, DNA Damage, DNA Repair, DNA, Single-Stranded, DNA-Binding Proteins, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Replication Protein A, Xeroderma Pigmentosum Group A Protein
Show Abstract · Added March 11, 2020
The XPA protein functions together with the single-stranded DNA (ssDNA) binding protein RPA as the central scaffold to ensure proper positioning of repair factors in multi-protein nucleotide excision repair (NER) machinery. We previously determined the structure of a short motif in the disordered XPA N-terminus bound to the RPA32C domain. However, a second contact between the XPA DNA-binding domain (XPA DBD) and the RPA70AB tandem ssDNA-binding domains, which is likely to influence the orientation of XPA and RPA on the damaged DNA substrate, remains poorly characterized. NMR was used to map the binding interfaces of XPA DBD and RPA70AB. Combining NMR and X-ray scattering data with comprehensive docking and refinement revealed how XPA DBD and RPA70AB orient on model NER DNA substrates. The structural model enabled design of XPA mutations that inhibit the interaction with RPA70AB. These mutations decreased activity in cell-based NER assays, demonstrating the functional importance of XPA DBD-RPA70AB interaction. Our results inform ongoing controversy about where XPA is bound within the NER bubble, provide structural insights into the molecular basis for malfunction of disease-associated XPA missense mutations, and contribute to understanding of the structure and mechanical action of the NER machinery.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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11 MeSH Terms
Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link.
Thompson PS, Amidon KM, Mohni KN, Cortez D, Eichman BF
(2019) Nat Struct Mol Biol 26: 613-618
MeSH Terms: Crystallography, X-Ray, DNA Repair, DNA Replication, DNA, Single-Stranded, DNA-Binding Proteins, Escherichia coli, Escherichia coli Proteins, Humans, Molecular Docking Simulation, Protein Conformation, Thiazolidines
Show Abstract · Added August 26, 2019
Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.
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11 MeSH Terms
Extensive loss of cell-cycle and DNA repair genes in an ancient lineage of bipolar budding yeasts.
Steenwyk JL, Opulente DA, Kominek J, Shen XX, Zhou X, Labella AL, Bradley NP, Eichman BF, Čadež N, Libkind D, DeVirgilio J, Hulfachor AB, Kurtzman CP, Hittinger CT, Rokas A
(2019) PLoS Biol 17: e3000255
MeSH Terms: Base Sequence, Cell Cycle, DNA Damage, DNA Repair, Evolution, Molecular, Genes, Fungal, Phenotype, Phylogeny, Saccharomycetales
Show Abstract · Added August 26, 2019
Cell-cycle checkpoints and DNA repair processes protect organisms from potentially lethal mutational damage. Compared to other budding yeasts in the subphylum Saccharomycotina, we noticed that a lineage in the genus Hanseniaspora exhibited very high evolutionary rates, low Guanine-Cytosine (GC) content, small genome sizes, and lower gene numbers. To better understand Hanseniaspora evolution, we analyzed 25 genomes, including 11 newly sequenced, representing 18/21 known species in the genus. Our phylogenomic analyses identify two Hanseniaspora lineages, a faster-evolving lineage (FEL), which began diversifying approximately 87 million years ago (mya), and a slower-evolving lineage (SEL), which began diversifying approximately 54 mya. Remarkably, both lineages lost genes associated with the cell cycle and genome integrity, but these losses were greater in the FEL. E.g., all species lost the cell-cycle regulator WHIskey 5 (WHI5), and the FEL lost components of the spindle checkpoint pathway (e.g., Mitotic Arrest-Deficient 1 [MAD1], Mitotic Arrest-Deficient 2 [MAD2]) and DNA-damage-checkpoint pathway (e.g., Mitosis Entry Checkpoint 3 [MEC3], RADiation sensitive 9 [RAD9]). Similarly, both lineages lost genes involved in DNA repair pathways, including the DNA glycosylase gene 3-MethylAdenine DNA Glycosylase 1 (MAG1), which is part of the base-excision repair pathway, and the DNA photolyase gene PHotoreactivation Repair deficient 1 (PHR1), which is involved in pyrimidine dimer repair. Strikingly, the FEL lost 33 additional genes, including polymerases (i.e., POLymerase 4 [POL4] and POL32) and telomere-associated genes (e.g., Repressor/activator site binding protein-Interacting Factor 1 [RIF1], Replication Factor A 3 [RFA3], Cell Division Cycle 13 [CDC13], Pbp1p Binding Protein [PBP2]). Echoing these losses, molecular evolutionary analyses reveal that, compared to the SEL, the FEL stem lineage underwent a burst of accelerated evolution, which resulted in greater mutational loads, homopolymer instabilities, and higher fractions of mutations associated with the common endogenously damaged base, 8-oxoguanine. We conclude that Hanseniaspora is an ancient lineage that has diversified and thrived, despite lacking many otherwise highly conserved cell-cycle and genome integrity genes and pathways, and may represent a novel, to our knowledge, system for studying cellular life without them.
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9 MeSH Terms
The abundant DNA adduct -methyl deoxyguanosine contributes to miscoding during replication by human DNA polymerase η.
Njuma OJ, Su Y, Guengerich FP
(2019) J Biol Chem 294: 10253-10265
MeSH Terms: DNA Adducts, DNA Damage, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Deoxyguanosine, Humans, Molecular Structure
Show Abstract · Added March 3, 2020
Aside from abasic sites and ribonucleotides, the DNA adduct -methyl deoxyguanosine ( -CH dG) is one of the most abundant lesions in mammalian DNA. Because -CH dG is unstable, leading to deglycosylation and ring-opening, its miscoding potential is not well-understood. Here, we employed a 2'-fluoro isostere approach to synthesize an oligonucleotide containing an analog of this lesion ( -CH 2'-F dG) and examined its miscoding potential with four Y-family translesion synthesis DNA polymerases (pols): human pol (hpol) η, hpol κ, and hpol ι and Dpo4 from the archaeal thermophile We found that hpol η and Dpo4 can bypass the -CH 2'-F dG adduct, albeit with some stalling, but hpol κ is strongly blocked at this lesion site, whereas hpol ι showed no distinction with the lesion and the control templates. hpol η yielded the highest level of misincorporation opposite the adduct by inserting dATP or dTTP. Moreover, hpol η did not extend well past an -CH 2'-F dG:dT mispair. MS-based sequence analysis confirmed that hpol η catalyzes mainly error-free incorporation of dC, with misincorporation of dA and dG in 5-10% of products. We conclude that -CH 2'-F dG and, by inference, -CH dG have miscoding and mutagenic potential. The level of misincorporation arising from this abundant adduct can be considered as potentially mutagenic as a highly miscoding but rare lesion.
© 2019 Njuma et al.
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MeSH Terms
Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.
Sekhar KR, Wang J, Freeman ML, Kirschner AN
(2019) PLoS One 14: e0214670
MeSH Terms: Aged, Animals, Cell Line, Tumor, Cell Proliferation, DNA Damage, DNA Repair, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Nude, Mice, Transgenic, Phenylthiohydantoin, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Radiation Tolerance, Radiation-Sensitizing Agents, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.
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19 MeSH Terms
HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA.
Mohni KN, Wessel SR, Zhao R, Wojciechowski AC, Luzwick JW, Layden H, Eichman BF, Thompson PS, Mehta KPM, Cortez D
(2019) Cell 176: 144-153.e13
MeSH Terms: 5-Methylcytosine, Apurinic Acid, DNA, DNA Damage, DNA Repair, DNA Replication, DNA, Single-Stranded, DNA-Binding Proteins, Endonucleases, Escherichia coli, Polynucleotides, Proliferating Cell Nuclear Antigen
Show Abstract · Added August 26, 2019
Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its E. coli ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.
Copyright © 2018 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Structural Biology of the HEAT-Like Repeat Family of DNA Glycosylases.
Shi R, Shen XX, Rokas A, Eichman BF
(2018) Bioessays 40: e1800133
MeSH Terms: Archaea, Bacteria, Crystallography, X-Ray, DNA, DNA Damage, DNA Glycosylases, DNA Repair, Eukaryota, Protein Conformation
Show Abstract · Added August 26, 2019
DNA glycosylases remove aberrant DNA nucleobases as the first enzymatic step of the base excision repair (BER) pathway. The alkyl-DNA glycosylases AlkC and AlkD adopt a unique structure based on α-helical HEAT repeats. Both enzymes identify and excise their substrates without a base-flipping mechanism used by other glycosylases and nucleic acid processing proteins to access nucleobases that are otherwise stacked inside the double-helix. Consequently, these glycosylases act on a variety of cationic nucleobase modifications, including bulky adducts, not previously associated with BER. The related non-enzymatic HEAT-like repeat (HLR) proteins, AlkD2, and AlkF, have unique nucleic acid binding properties that expand the functions of this relatively new protein superfamily beyond DNA repair. Here, we review the phylogeny, biochemistry, and structures of the HLR proteins, which have helped broaden our understanding of the mechanisms by which DNA glycosylases locate and excise chemically modified DNA nucleobases.
© 2018 WILEY Periodicals, Inc.
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Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.
Ding L, Bailey MH, Porta-Pardo E, Thorsson V, Colaprico A, Bertrand D, Gibbs DL, Weerasinghe A, Huang KL, Tokheim C, Cortés-Ciriano I, Jayasinghe R, Chen F, Yu L, Sun S, Olsen C, Kim J, Taylor AM, Cherniack AD, Akbani R, Suphavilai C, Nagarajan N, Stuart JM, Mills GB, Wyczalkowski MA, Vincent BG, Hutter CM, Zenklusen JC, Hoadley KA, Wendl MC, Shmulevich L, Lazar AJ, Wheeler DA, Getz G, Cancer Genome Atlas Research Network
(2018) Cell 173: 305-320.e10
MeSH Terms: Carcinogenesis, DNA Repair, Databases, Genetic, Genes, Neoplasm, Genomics, Humans, Metabolic Networks and Pathways, Microsatellite Instability, Mutation, Neoplasms, Transcriptome, Tumor Microenvironment
Show Abstract · Added October 30, 2019
The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.
Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, Fan H, Shen H, Way GP, Greene CS, Liu Y, Akbani R, Feng B, Donehower LA, Miller C, Shen Y, Karimi M, Chen H, Kim P, Jia P, Shinbrot E, Zhang S, Liu J, Hu H, Bailey MH, Yau C, Wolf D, Zhao Z, Weinstein JN, Li L, Ding L, Mills GB, Laird PW, Wheeler DA, Shmulevich I, Cancer Genome Atlas Research Network, Monnat RJ, Xiao Y, Wang C
(2018) Cell Rep 23: 239-254.e6
MeSH Terms: Cell Line, Tumor, DNA Damage, Gene Silencing, Genome, Human, Humans, Loss of Heterozygosity, Machine Learning, Mutation, Neoplasms, Recombinational DNA Repair, Tumor Suppressor Proteins
Show Abstract · Added October 30, 2019
DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC.
Shi R, Mullins EA, Shen XX, Lay KT, Yuen PK, David SS, Rokas A, Eichman BF
(2018) EMBO J 37: 63-74
MeSH Terms: Adenine, Alkylation, Amino Acid Sequence, Bacillus cereus, Catalytic Domain, Crystallography, X-Ray, DNA Adducts, DNA Damage, DNA Glycosylases, DNA Repair, Models, Molecular, Protein Conformation, Sequence Homology
Show Abstract · Added March 21, 2018
DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA). Here, we describe how AlkC selects for and excises 3mA using a non-base-flipping strategy distinct from that of AlkD. A crystal structure resembling a catalytic intermediate complex shows how AlkC uses unique HLR and immunoglobulin-like domains to induce a sharp kink in the DNA, exposing the damaged nucleobase to active site residues that project into the DNA This active site can accommodate and excise N3-methylcytosine (3mC) and N1-methyladenine (1mA), which are also repaired by AlkB-catalyzed oxidative demethylation, providing a potential alternative mechanism for repair of these lesions in bacteria.
© 2017 The Authors.
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13 MeSH Terms