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https://www.readbyqxmd.com/read/28079002/neurotoxicity-associated-with-platinum-based-anti-cancer-agents-what-are-the-implications-of-copper-transporters
#1
Vanesa Stojanovska, Rachel McQuade, Emma Rybalka, Kulmira Nurgali
Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin, are an important class of drugs used in clinical setting to treat a variety of cancers. The cytotoxic efficacy of these drugs is mediated by the formation of interstrand and intrastrand crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons. Although all platinum-based agents form similar DNA adducts, they are quite different in terms of activation, systemic toxicity and tolerance...
January 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28075014/knockdown-of-rev3-synergizes-with-atr-inhibition-to-promote-apoptosis-induced-by-cisplatin-in-lung-cancer-cells
#2
He-Guo Jiang, Ping Chen, Jin-Yu Su, Ming Wu, Hai Qian, Yi Wang, Jian Li
It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase ζ, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear...
January 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27995412/hucop1-contributes-to-the-regulation-of-dna-repair-in-keratinocytes
#3
B Fazekas, M P Carty, I Németh, L Kemény, M Széll, É Ádám
We have previously demonstrated that the E3 ligase Human Constitutive Photomorphogenic Protein (huCOP1) is expressed in human keratinocytes and negatively regulates p53. The MutS homolog 2 (MSH2) protein plays a central role in DNA MMR mechanism and is implicated in the cellular response to anticancer agents, such as cisplatin. Our aim was to clarify whether huCOP1 plays a role in DNA MMR by affecting MSH2 protein level in human keratinocytes. To define the role of huCOP1 in DNA mismatch repair, we determined whether huCOP1 affects MSH2 abundance...
December 19, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27989548/dna-replication-and-inter-strand-crosslink-repair-symmetric-activation-of-dimeric-nanomachines
#4
Paolo Swuec, Alessandro Costa
Eukaryotic DNA replication initiation and the Fanconi anemia pathway of interstrand crosslink repair both revolve around the recruitment of a set of DNA-processing factors onto a dimeric protein complex, which functions as a loading platform (MCM and FANCI-FANCD2 respectively). Here we compare and contrast the two systems, identifying a set of unresolved mechanistic questions. How is the dimeric loading platform assembled on the DNA? How can equivalent covalent modification of both factors in a dimer be achieved? Are multicomponent DNA-interacting machines built symmetrically around their dimeric loading platform? Recent biochemical reconstitution studies are starting to shed light on these issues...
November 10, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27986592/the-fa-core-complex-contains-a-homo-dimeric-catalytic-module-for-the-symmetric-mono-ubiquitination-of-fanci-fancd2
#5
Paolo Swuec, Ludovic Renault, Aaron Borg, Fenil Shah, Vincent J Murphy, Sylvie van Twest, Bram Snijders, Andrew J Deans, Alessandro Costa
Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear...
December 9, 2016: Cell Reports
https://www.readbyqxmd.com/read/27978798/combination-platinum-based-and-dna-damage-response-targeting-cancer-therapy-evolution-and-future-directions
#6
Spyridon P Basourakos, Likun Li, Ana M Aparicio, Paul G Corn, Jeri Kim, Timothy C Thompson
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Alkylating factors, i.e., interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR) including DNA repair, and mainly involves the nucleotide excision repair (NER) pathway. When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis...
December 14, 2016: Current Medicinal Chemistry
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27448776/identification-of-the-first-small-molecule-inhibitor-of-the-rev7-dna-repair-protein-interaction
#20
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
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