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https://www.readbyqxmd.com/read/28938088/small-molecule-inhibitors-targeting-dna-repair-and-dna-repair-deficiency-in-research-and-cancer-therapy
#1
REVIEW
Sarah R Hengel, M Ashley Spies, Maria Spies
To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28936799/proteomic-features-of-colorectal-cancer-identify-tumor-subtypes-independent-of-oncogenic-mutations-and-independently-predict-relapse-free-survival
#2
Callisia N Clarke, Michael S Lee, Wei Wei, Ganiraju Manyam, Zhi-Qin Jiang, Yiling Lu, Jeffrey Morris, Bradley Broom, David Menter, Eduardo Vilar-Sanchez, Kanwal Raghav, Cathy Eng, George J Chang, Iris Simon, Rene Bernards, Michael Overman, Gordon B Mills, Dipen Maru, Scott Kopetz
BACKGROUND: The directed study of the functional proteome in colorectal cancer (CRC) has identified critical protein markers and signaling pathways; however, the prognostic relevance of many of these proteins remains unclear. METHODS: We determined the prognostic implications of the functional proteome in 263 CRC tumor samples from patients treated at MD Anderson Cancer Center (MDACC) and 462 patients from The Cancer Genome Atlas (TCGA) to identify patterns of protein expression that drive tumorigenesis...
September 21, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/28936205/homologous-recombination-in-protozoan-parasites-and-recombinase-inhibitors
#3
REVIEW
Andrew A Kelso, Sarah M Waldvogel, Adam J Luthman, Michael G Sehorn
Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that utilizes a homologous template to fully repair the damaged DNA. HR is critical to maintain genome stability and to ensure genetic diversity during meiosis. A specialized class of enzymes known as recombinases facilitate the exchange of genetic information between sister chromatids or homologous chromosomes with the help of numerous protein accessory factors. The majority of the HR machinery is highly conserved among eukaryotes...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28934470/monitoring-replication-protein-a-rpa-dynamics-in-homologous-recombination-through-site-specific-incorporation-of-non-canonical-amino-acids
#4
Nilisha Pokhrel, Sofia Origanti, Eric Parker Davenport, Disha Gandhi, Kyle Kaniecki, Ryan A Mehl, Eric C Greene, Chris Dockendorff, Edwin Antony
An essential coordinator of all DNA metabolic processes is Replication Protein A (RPA). RPA orchestrates these processes by binding to single-stranded DNA (ssDNA) and interacting with several other DNA binding proteins. Determining the real-time kinetics of single players such as RPA in the presence of multiple DNA processors to better understand the associated mechanistic events is technically challenging. To overcome this hurdle, we utilized non-canonical amino acids and bio-orthogonal chemistry to site-specifically incorporate a chemical fluorophore onto a single subunit of heterotrimeric RPA...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28927196/the-intricate-interplay-between-msi-and-polymorphisms-of-dna-repair-enzymes-in-gastric-cancer-h-pylori-associated
#5
Isabelle Joyce de Lima Silva-Fernandes, Emanuele Silva de Oliveira, Juliana Carvalho Santos, Marcelo Lima Ribeiro, Adriana Camargo Ferrasi, Maria Inês de Moura Campos Pardini, Rommel Mário Rodriguez Burbano, Silvia Helena Barem Rabenhorst
Gastric cancer is the fourth most common type of cancer worldwide. Helicobacter pylori is a well-established risk factor and may cause injuries to genomic integrity through an inefficient DNA repair. This study aimed to examine the influence of polymorphisms in DNA repair enzymes using markers for microsatellite instability (MSI). Polymorphisms of DNA repair enzymes were detected by PCR-RFLP and MSI, by high resolution melt (HRM) analysis. Helicobacter pylori detection and genotyping were accomplished by PCR...
July 1, 2017: Mutagenesis
https://www.readbyqxmd.com/read/28927087/gimeracil-enhances-the-antitumor-effect-of-cisplatin-in-oral-squamous-cell-carcinoma-cells-in-vitro-and-in-vivo
#6
Koji Harada, Tarannum Ferdous, Toyoko Harada, Takanori Takenawa, Yoshiya Ueyama
Gimeracil or 5-chloro-2,4-dihydroxypyridine (CDHP) enhances the antitumor effects of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU. CDHP, as part of a combination therapy, was also reported to exert a radiosensitizing effect. Therefore, CDHP may have underlying mechanisms of action other than DPD inhibition. The focus of the present study was to investigate the antitumor effects of CDHP and cisplatin (CDDP) combination treatment in vitro and in vivo against oral squamous cell carcinoma (OSCC) tumors...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28926421/a-novel-hydroxyphenyl-hydrazone-derivate-ycl0426-inhibits-cancer-cell-proliferation-through-sequestering-iron
#7
Feifei Li, Long Long, Junhai Xiao, Chen Wang, Wei Li, Song Li, Changqi Zhao, Lili Wang
Cancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine-Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay...
September 18, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#8
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28919752/zinc-oxide-nanoparticles-induce-apoptosis-and-autophagy-in-human-ovarian-cancer-cells
#9
Ding-Ping Bai, Xi-Feng Zhang, Guo-Liang Zhang, Yi-Fan Huang, Sangiliyandi Gurunathan
BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are frequently used in industrial products such as paint, surface coating, and cosmetics, and recently, they have been explored in biologic and biomedical applications. Therefore, this study was undertaken to investigate the effect of ZnO NPs on cytotoxicity, apoptosis, and autophagy in human ovarian cancer cells (SKOV3). METHODS: ZnO NPs with a crystalline size of 20 nm were characterized with various analytical techniques, including ultraviolet-visible spectroscopy, X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, and atomic force microscopy...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28912486/the-homologous-recombination-machinery-orchestrates-post-replication-dna-repair-during-self-renewal-of-mouse-embryonic-stem-cells
#10
Eui-Hwan Choi, Seobin Yoon, Kyung-Soon Park, Keun P Kim
Embryonic stem (ES) cells require homologous recombination (HR) to cope with genomic instability caused during self-renewal. Here, we report expression dynamics and localization of endogenous HR factors in DNA break repair of ES cells. In addition, we analyzed gene expression patterns of HR-related factors at the transcript level with RNA-sequencing experiments. We showed that ES cells constitutively expressed diverse HR proteins throughout the cell cycle and that HR protein expression was not significantly changed even in the DNA damaging conditions...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28912125/blm-helicase-regulates-dna-repair-by-counteracting-rad51-loading-at-dna-double-strand-break-sites
#11
Dharm S Patel, Sarah M Misenko, Joonyoung Her, Samuel F Bunting
The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. We find that in cells expressing a mutant version of BRCA1, an essential HR factor, ablation of BLM rescues genomic integrity and cell survival in the presence of DNA double-strand breaks. Improved genomic integrity in these cells is linked to a substantial increase in the stability of RAD51 at DNA double-strand break sites and in the overall efficiency of HR...
September 14, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28894029/pari-regulates-stalled-replication-fork-processing-to-maintain-genome-stability-upon-replication-stress-in-mice
#12
Ayako L Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai, Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, Shinichiro Chuma
DNA replication is frequently perturbed by intrinsic as well as extrinsic genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain the genome integrity. We show here that PARI anti-recombinase plays an essential role to modulate the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent strand shortening that is regulated by RAD51 and MRE11...
September 11, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28891354/brca2-protects-mammalian-cells-from-heat-shock
#13
Yosuke Nakagawa, Atsuhisa Kajihara, Akihisa Takahashi, Akiho S Murata, Masaya Matsubayashi, Soichiro S Ito, Ichiro Ota, Takahiko Nakagawa, Masatoshi Hasegawa, Tadaaki Kirita, Takeo Ohnishi, Eiichiro Mori
PURPOSE: Heat shock induces DNA double-strand breaks (DSBs) in mammalian cells. Mammalian cells are capable of repairing DSBs by utilising the homologous recombination (HR) pathway. Breast cancer susceptibility gene 2 (BRCA2) is known to regulate the HR pathway. Here, we investigate the role of BRCA2 in repairing DNA damage induced by heat shock. MATERIALS AND METHODS: Chinese hamster lung fibroblast cell lines and human tongue squamous cell carcinoma SAS cells were used...
September 10, 2017: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/28886696/inhibition-of-pi3k-akt-mtor-pathway-sensitizes-endometrial-cancer-cell-lines-to-parp-inhibitors
#14
Charles-André Philip, Ido Laskov, Marie-Claude Beauchamp, Maud Marques, Oreekha Amin, Joanna Bitharas, Roy Kessous, Liron Kogan, Tahira Baloch, Walter H Gotlieb, Amber Yasmeen
BACKGROUND: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. METHODS: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay...
September 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28869605/suppression-of-sirt1-sensitizes-lung-cancer-cells-to-wee1-inhibitor-mk-1775-induced-dna-damage-and-apoptosis
#15
G Chen, B Zhang, H Xu, Y Sun, Y Shi, Y Luo, H Jia, F Wang
Lung cancer treatment remains a challenge for clinical practice and new therapeutic approaches are urgently needed. Loss of functional WEE1 kinase causes DNA replication stress, DNA damage and unscheduled mitotic entry due to elevated CDK activity. The selective WEE1 inhibitor MK-1775 synergize with DNA-damaging agent to inhibit cancer cell growth. Here we report that inhibition of Sirt1 deacetylase through small interfering RNA or selective inhibitor Ex527 greatly enhances MK-1775-induced growth inhibition and apoptosis in human lung cancer cells...
September 4, 2017: Oncogene
https://www.readbyqxmd.com/read/28860160/abro1-maintains-genome-stability-and-limits-replication-stress-by-protecting-replication-fork-stability
#16
Shengfeng Xu, Xiao Wu, Ling Wu, Andy Castillo, Jianxin Liu, Erin Atkinson, Atanu Paul, Dan Su, Katharina Schlacher, Yoshihiro Komatsu, M James You, Bin Wang
Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chromosome instability, and Abro1-null mice are tumor-prone. We show that Abro1 protects stalled replication fork stability by inhibiting DNA2 nuclease/WRN helicase-mediated degradation of stalled forks...
July 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28858227/the-role-of-palb2-in-the-dna-damage-response-and-cancer-predisposition
#17
REVIEW
Thales C Nepomuceno, Giuliana De Gregoriis, Francisco M Bastos de Oliveira, Guilherme Suarez-Kurtz, Alvaro N Monteiro, Marcelo A Carvalho
The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. Since its identification as a BRCA2 interacting partner, PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers...
August 31, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28855448/caffeine-has-a-synergistic-anticancer-effect-with-cisplatin-via-inhibiting-fanconi-anemia-group-d2-protein-monoubiquitination-in-hepatocellular-carcinoma-cells
#18
Yuichiro Oda, Muneaki Hidaka, Akito Suzuki
Cisplatin is an anticancer agent and induces DNA interstrand cross-links (ICLs). ICLs activate various signaling processes and induce DNA repair pathways, including the Fanconi anemia (FA) pathway. FA complementation group D2 (FANCD2) is monoubiquitinated in response to DNA damage, leading to activation of the DNA double-strand-break repair protein, RAD51. Caffeine increases the anticancer activity of cisplatin by inhibiting DNA repair; however, details of the mechanism remain unclear. We investigated the mechanism responsible for the synergistic anticancer effect of cisplatin and caffeine in HepG2 human hepatocellular carcinoma cells, focusing on the FA pathway...
August 31, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28853250/-rs-1-enhanced-the-efficiency-of-crispr-cas9-mediated-knock-in-of-human-lactoferrin
#19
Wenjun Zhou, Rihong Guo, Mingtian Deng, Feng Wang, Yanli Zhang
This study aims to knock out the goat β-lactoglobulin (BLG) gene using CRISPR-Cas9 system and knock in human lactoferrin (hLF) at the BLG locus, and further study the effect of RAD51 stimulatory compound (RS-1) on homologous recombination efficiency. First, we designed an sgRNA targeting the first exon of goat BLG gene and constructed a co-expression vector pCas9-sgBLG. This sgRNA vector was then transfected into goat ear fibroblasts (GEFs), and the target region was examined by T7EN1 assay and sequencing...
August 25, 2017: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
https://www.readbyqxmd.com/read/28852018/ape1-guides-dna-repair-pathway-choice-that-is-associated-with-drug-tolerance-in-glioblastoma
#20
Thomas Ströbel, Sibylle Madlener, Serkan Tuna, Sarah Vose, Tonny Lagerweij, Thomas Wurdinger, Klemens Vierlinger, Adelheid Wöhrer, Brendan D Price, Bruce Demple, Okay Saydam, Nurten Saydam
Ape1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells...
August 29, 2017: Scientific Reports
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