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https://www.readbyqxmd.com/read/28174693/fanconi-anemia-protein-fancd2-is-activated-by-aicar-a-modulator-of-ampk-and-cellular-energy-metabolism
#1
Min Jeong Chun, Hana Choi, Dong Wha Jun, Sunshin Kim, Yong-Nyun Kim, Soo-Youl Kim, Chang-Hun Lee
FANCD2 is a pivotal molecule in the pathogenesis of Fanconi anemia (FA), an autosomal recessive human syndrome with diverse clinical phenotypes, including cancer predisposition, short stature, and hematological abnormalities. In our previous study, we detected the functional association of FANC proteins, whose mutations are responsible for the onset of FA, with AMPK in response to DNA interstrand crosslinking lesions. Because AMPK is well known as a critical sensing molecule for cellular energy levels, we checked whether FANCD2 activation occurs after treatments affecting AMPK and/or cellular energy status...
February 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28154196/dna-repair-in-drosophila-mutagens-models-and-missing-genes
#2
Jeff Sekelsky
The numerous processes that damage DNA are counterbalanced by a complex network of repair pathways that, collectively, can mend diverse types of damage. Insights into these pathways have come from studies in many different organisms, including Drosophila melanogaster Indeed, the first ideas about chromosome and gene repair grew out of Drosophila research on the properties of mutations produced by ionizing radiation and mustard gas. Numerous methods have been developed to take advantage of Drosophila genetic tools to elucidate repair processes in whole animals, organs, tissues, and cells...
February 2017: Genetics
https://www.readbyqxmd.com/read/28143714/chloroethylating-nitrosoureas-in-cancer-therapy-dna-damage-repair-and-cell-death-signaling
#3
REVIEW
Teodora Nikolova, Wynand P Roos, Oliver H Krämer, Herwig M Strik, Bernd Kaina
Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy...
January 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28130555/xpf-knockout-via-crispr-cas9-reveals-that-ercc1-is-retained-in-the-cytoplasm-without-its-heterodimer-partner-xpf
#4
Janin Lehmann, Christina Seebode, Sabine Smolorz, Steffen Schubert, Steffen Emmert
The XPF/ERCC1 heterodimeric complex is essentially involved in nucleotide excision repair (NER), interstrand crosslink (ICL), and double-strand break repair. Defects in XPF lead to severe diseases like xeroderma pigmentosum (XP). Up until now, XP-F patient cells have been utilized for functional analyses. Due to the multiple roles of the XPF/ERCC1 complex, these patient cells retain at least one full-length allele and residual repair capabilities. Despite the essential function of the XPF/ERCC1 complex for the human organism, we successfully generated a viable immortalised human XPF knockout cell line with complete loss of XPF using the CRISPR/Cas9 technique in fetal lung fibroblasts (MRC5Vi cells)...
January 27, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28110804/differential-role-of-base-excision-repair-proteins-in-mediating-cisplatin-cytotoxicity
#5
Akshada Sawant, Ashley M Floyd, Mohan Dangeti, Wen Lei, Robert W Sobol, Steve M Patrick
Interstrand crosslinks (ICLs) are covalent lesions formed by cisplatin. The mechanism for the processing and removal of ICLs by DNA repair proteins involves nucleotide excision repair (NER), homologous recombination (HR) and fanconi anemia (FA) pathways. In this report, we monitored the processing of a flanking uracil adjacent to a cisplatin ICL by the proteins involved in the base excision repair (BER) pathway. Using a combination of extracts, purified proteins, inhibitors, functional assays and cell culture studies, we determined the specific BER proteins required for processing a DNA substrate with a uracil adjacent to a cisplatin ICL...
January 11, 2017: DNA Repair
https://www.readbyqxmd.com/read/28079002/neurotoxicity-associated-with-platinum-based-anti-cancer-agents-what-are-the-implications-of-copper-transporters
#6
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
#7
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
#8
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...
March 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27989548/dna-replication-and-inter-strand-crosslink-repair-symmetric-activation-of-dimeric-nanomachines
#9
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
#10
Paolo Swuec, Ludovic Renault, Aaron Borg, Fenil Shah, Vincent J Murphy, Sylvie van Twest, Ambrosius P 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...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/27978798/combination-platinum-based-and-dna-damage-response-targeting-cancer-therapy-evolution-and-future-directions
#11
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
#12
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
#13
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
#14
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...
February 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27819275/the-pten-phosphatase-functions-cooperatively-with-the-fanconi-anemia-proteins-in-dna-crosslink-repair
#15
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
#16
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
#17
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...
January 2, 2017: 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
#18
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
#19
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
#20
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
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