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Interstrand crosslink

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https://www.readbyqxmd.com/read/27924002/sfpq%C3%A2-nono-and-xlf-function-separately-and-together-to-promote-dna-double-strand-break-repair-via-canonical-nonhomologous-end-joining
#1
Lahcen Jaafar, Zhentian Li, Shuyi Li, William S Dynan
A complex of two related mammalian proteins, SFPQ and NONO, promotes DNA double-strand break repair via the canonical nonhomologous end joining (c-NHEJ) pathway. However, its mechanism of action is not fully understood. Here we describe an improved SFPQ•NONO-dependent in vitro end joining assay. We use this system to demonstrate that the SFPQ•NONO complex substitutes in vitro for the core c-NHEJ factor, XLF. Results are consistent with a model where SFPQ•NONO promotes sequence-independent pairing of DNA substrates, albeit in a way that differs in detail from XLF...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27911399/tools-to-study-the-role-of-architectural-protein-hmgb1-in-the-processing-of-helix-distorting-site-specific-dna-interstrand-crosslinks
#2
Anirban Mukherjee, Karen M Vasquez
High mobility group box 1 (HMGB1) protein is a non-histone architectural protein that is involved in regulating many important functions in the genome, such as transcription, DNA replication, and DNA repair. HMGB1 binds to structurally distorted DNA with higher affinity than to canonical B-DNA. For example, we found that HMGB1 binds to DNA interstrand crosslinks (ICLs), which covalently link the two strands of the DNA, cause distortion of the helix, and if left unrepaired can cause cell death. Due to their cytotoxic potential, several ICL-inducing agents are currently used as chemotherapeutic agents in the clinic...
November 10, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27834954/strong-antitumor-synergy-between-dna-crosslinking-and-hsp90-inhibition-causes-massive-premitotic-dna-fragmentation-in-ovarian-cancer-cells
#3
Daniela Kramer, Nadine Stark, Ramona Schulz-Heddergott, Norman Erytch, Shelley Edmunds, Laura Roßmann, Holger Bastians, Nicole Concin, Ute M Moll, Matthias Dobbelstein
All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation...
November 11, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27819275/the-pten-phosphatase-functions-cooperatively-with-the-fanconi-anemia-proteins-in-dna-crosslink-repair
#4
Elizabeth A Vuono, Ananda Mukherjee, David A Vierra, Morganne M Adroved, Charlotte Hodson, Andrew J Deans, Niall G Howlett
Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci...
November 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27738139/the-multifaceted-influence-of-histone-deacetylases-on-dna-damage-signalling-and-dna-repair
#5
Wynand Paul Roos, Andrea Krumm
Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD(+) dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27687866/genetic-controls-of-dna-damage-avoidance-in-response-to-acetaldehyde-in-fission-yeast
#6
Chiaki Noguchi, Grant Grothusen, Vinesh Anandarajan, Marta Martínez-Lage García, Daniel Terlecky, Krysten Corzo, Katsunori Tanaka, Hiroshi Nakagawa, Eishi Noguchi
Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde...
September 29, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27650543/identification-of-small-molecule-inhibitors-of-ercc1-xpf-that-inhibit-dna-repair-and-potentiate-cisplatin-efficacy-in-cancer-cells
#7
Sanjeevani Arora, Joshua Heyza, Hao Zhang, Vivian Kalman-Maltese, Kristin Tillison, Ashley M Floyd, Elaine M Chalfin, Gerold Bepler, Steve M Patrick
ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range...
September 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27595121/fanconi-anemia-pathway-regulates-convergent-transcription-induced-cell-death-at-trinucleotide-repeats-in-human-cells
#8
Nimrat Chatterjee, Yunfu Lin, John H Wilson
Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology...
May 2016: Postdoc Journal: a Journal of Postdoctoral Research and Postdoctoral Affairs
https://www.readbyqxmd.com/read/27587838/the-role-of-adp-ribosylation-in-regulating-dna-interstrand-crosslink-repair
#9
Alasdair R Gunn, Benito Banos-Pinero, Peggy Paschke, Luis Sanchez-Pulido, Antonio Ariza, Joseph Day, Mehera Emrich, David Leys, Chris P Ponting, Ivan Ahel, Nicholas D Lakin
ADP-ribosylation by ADP-ribosyltransferases (ARTs) has a well-established role in DNA strand break repair by promoting enrichment of repair factors at damage sites through ADP-ribose interaction domains. Here, we exploit the simple eukaryote Dictyostelium to uncover a role for ADP-ribosylation in regulating DNA interstrand crosslink repair and redundancy of this pathway with non-homologous end-joining (NHEJ). In silico searches were used to identify a protein that contains a permutated macrodomain (which we call aprataxin/APLF-and-PNKP-like protein; APL)...
October 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27581636/efficient-thymidine-selective-dna-interstrand-photo-activated-crosslinking-by-the-6-thioguanine-connected-via-an-ethylene-linker-to-the-2-deoxyribose-unit
#10
Takamasa Nishioka, Ikuya Oshiro, Kazumitsu Onizuka, Yosuke Taniguchi, Shigeki Sasaki
Cross-linking is a widely-used technology in the studies of DNA, RNA and their complexes with proteins. Intrinsically active alkylating moieties and photo-activated agents are chemically or enzymatically incorporated into nucleic acids. Thionucleobases resemble the corresponding natural bases, and form cross-links by UVA irradiation. They form cross-links only with a site in close contact, thereby allowing identification of the contacts within the nucleic acids and/or between the nucleic acids and proteins in complex nucleoprotein assemblies...
2016: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27573016/cho-endonuclease-functions-during-dna-interstrand-cross-link-repair-in-escherichia-coli
#11
Anthonige Vidya Perera, James Brian Mendenhall, Charmain Tan Courcelle, Justin Courcelle
: DNA interstrand cross-links are complex lesions that covalently link both strands of the duplex DNA. Lesion removal is proposed to be initiated via the UvrABC nucleotide excision repair complex; however, less is known about the subsequent steps of this complex repair pathway. In this study, we characterized the contribution of nucleotide excision repair mutants to survival in the presence of psoralen-induced damage. Unexpectedly, we observed that the nucleotide excision repair mutants exhibit differential sensitivity to psoralen-induced damage, with uvrC mutants being less sensitive than either uvrA or uvrB We show that Cho, an alternative endonuclease, acts with UvrAB and is responsible for the reduced hypersensitivity of uvrC mutants...
November 15, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27474153/targeting-homologous-recombination-by-pharmacological-inhibitors-enhances-the-killing-response-of-glioblastoma-cells-treated-with-alkylating-drugs
#12
Nancy Berte, Andrea Piée-Staffa, Nadine Piecha, Mengwan Wang, Kerstin Borgmann, Bernd Kaina, Teodora Nikolova
Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O(6) -chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways...
July 29, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27449087/amp-activated-protein-kinase-is-involved-in-the-activation-of-the-fanconi-anemia-brca-pathway-in-response-to-dna-interstrand-crosslinks
#13
Min Jeong Chun, Sunshin Kim, Soo Kyung Hwang, Bong Sub Kim, Hyoun Geun Kim, Hae In Choi, Jong Heon Kim, Sung Ho Goh, Chang-Hun Lee
Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments...
July 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27448776/identification-of-the-first-small-molecule-inhibitor-of-the-rev7-dna-repair-protein-interaction
#14
Marcelo L Actis, Nigus D Ambaye, Benjamin J Evison, Youming Shao, Murugendra Vanarotti, Akira Inoue, Ezelle T McDonald, Sotaro Kikuchi, Richard Heath, Kodai Hara, Hiroshi Hashimoto, Naoaki Fujii
DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed...
September 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27405460/the-fancd2-fanci-complex-is-recruited-to-dna-interstrand-crosslinks-before-monoubiquitination-of-fancd2
#15
Chih-Chao Liang, Zhuolun Li, David Lopez-Martinez, William V Nicholson, Catherine Vénien-Bryan, Martin A Cohn
The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2-FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2-FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain...
2016: Nature Communications
https://www.readbyqxmd.com/read/27373334/brca1-fancd2-brg1-driven-dna-repair-stabilizes-the-differentiation-state-of-human-mammary-epithelial-cells
#16
Hua Wang, Brian Bierie, Andrew G Li, Shailja Pathania, Kimberly Toomire, Stoil D Dimitrov, Ben Liu, Rebecca Gelman, Anita Giobbie-Hurder, Jean Feunteun, Kornelia Polyak, David M Livingston
An abnormal differentiation state is common in BRCA1-deficient mammary epithelial cells, but the underlying mechanism is unclear. Here, we report a convergence between DNA repair and normal, cultured human mammary epithelial (HME) cell differentiation. Surprisingly, depleting BRCA1 or FANCD2 (Fanconi anemia [FA] proteins) or BRG1, a mSWI/SNF subunit, caused HME cells to undergo spontaneous epithelial-to-mesenchymal transition (EMT) and aberrant differentiation. This also occurred when wild-type HMEs were exposed to chemicals that generate DNA interstrand crosslinks (repaired by FA proteins), but not in response to double-strand breaks...
July 21, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27350828/mechanisms-of-interstrand-dna-crosslink-repair-and-human-disorders
#17
REVIEW
Satoru Hashimoto, Hirofumi Anai, Katsuhiro Hanada
Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion affects both strands of the DNA, the ICL repair is not simple. So far, nucleotide excision repair (NER), structure-specific endonucleases, translesion DNA synthesis (TLS), homologous recombination (HR), and factors responsible for Fanconi anemia (FA) are identified to be involved in ICL repair. Since the presence of ICL lesions causes severe defects in transcription and DNA replication, mutations in these DNA repair pathways give rise to a various hereditary disorders...
2016: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
https://www.readbyqxmd.com/read/27342280/g-quadruplex-recognition-and-remodeling-by-the-fancj-helicase
#18
Colin G Wu, Maria Spies
Guanine rich nucleic acid sequences can form G-quadruplex (G4) structures that interfere with DNA replication, repair and RNA transcription. The human FANCJ helicase contributes to maintaining genomic integrity by promoting DNA replication through G4-forming DNA regions. Here, we combined single-molecule and ensemble biochemical analysis to show that FANCJ possesses a G4-specific recognition site. Through this interaction, FANCJ targets G4-containing DNA where its helicase and G4-binding activities enable repeated rounds of stepwise G4-unfolding and refolding...
June 24, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27326450/dark-hydrazone-fluorescence-labeling-agents-enable-imaging-of-cellular-aldehydic-load
#19
Lik Hang Yuen, Nivedita S Saxena, Hyun Shin Park, Kenneth Weinberg, Eric T Kool
Aldehydes are key intermediates in many cellular processes, from endogenous metabolic pathways like glycolysis to undesired exogenously induced processes such as lipid peroxidation and DNA interstrand cross-linking. Alkyl aldehydes are well documented to be cytotoxic, affecting the functions of DNA and protein, and their levels are tightly regulated by the oxidative enzyme ALDH2. Mutations in this enzyme are associated with cardiac damage, diseases such as Fanconi anemia (FA), and cancer. Many attempts have been made to identify and quantify the overall level of these alkyl aldehydes inside cells, yet there are few practical methods available to detect and monitor these volatile aldehydes in real time...
August 19, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27311543/involvement-of-translesion-synthesis-dna-polymerases-in-dna-interstrand-crosslink-repair
#20
REVIEW
Upasana Roy, Orlando D Schärer
DNA interstrand crosslinks (ICLs) covalently join the two strands of a DNA duplex and block essential processes such as DNA replication and transcription. Several important anti-tumor drugs such as cisplatin and nitrogen mustards exert their cytotoxicity by forming ICLs. However, multiple complex pathways repair ICLs and these are thought to contribute to the development of resistance towards ICL-inducing agents. While the understanding of many aspects of ICL repair is still rudimentary, studies in recent years have provided significant insights into the pathways of ICL repair...
August 2016: DNA Repair
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