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Neha J Pancholi, Matthew D Weitzman
During viral replication in the nucleus, the DNA genomes of adenoviruses are accessible to cellular DNA-binding proteins. Human adenovirus type 5 (Ad5) targets the cellular Mre11-Rad50-Nbs1 complex (MRN) to evade detection by the DNA damage response (DDR). Ad5 mutants that cannot target MRN have reduced viral propagation. Previous studies showed that diverse adenovirus serotypes interact differently with MRN. While these studies revealed diverse MRN interactions among serotypes, it remains unclear how these differences influence viral replication...
March 13, 2018: Virology
Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
Dehong Huang, Lei Jin, Zhengkang Li, Ji Wu, Ni Zhang, Dianrong Zhou, Xiaorong Ni, Tieying Hou
Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Joung-Sun Park, Ho-Jun Jeon, Jung-Hoon Pyo, Young-Shin Kim, Mi-Ae Yoo
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging...
March 7, 2018: Aging
Mariarosaria De Falco, Federica Massa, Mosè Rossi, Mariarita De Felice
ATPase/Helicases and nucleases play important roles in DNA end-resection, a critical step during homologous recombination repair in all organisms. In hyperthermophilic archaea the exo-endonuclease NurA and the ATPase HerA cooperate with the highly conserved Mre11-Rad50 complex in 3' single-stranded DNA (ssDNA) end processing to coordinate repair of double-stranded DNA breaks. Little is known, however, about the assembly mechanism and activation of the HerA-NurA complex. In this study we demonstrate that the NurA exonuclease activity is inhibited by the Sulfolobus solfataricus RecQ-like Hel112 helicase...
February 27, 2018: Extremophiles: Life Under Extreme Conditions
Valentine Mosbach, Lucie Poggi, David Viterbo, Marine Charpentier, Guy-Franck Richard
Trinucleotide repeat expansions involving CTG/CAG triplets are responsible for several neurodegenerative disorders, including myotonic dystrophy and Huntington's disease. Because expansions trigger the disease, contracting repeat length could be a possible approach to gene therapy for these disorders. Here, we show that a TALEN-induced double-strand break was very efficient at contracting expanded CTG repeats in yeast. We show that RAD51, POL32, and DNL4 are dispensable for double-strand break repair within CTG repeats, the only required genes being RAD50, SAE2, and RAD52...
February 20, 2018: Cell Reports
Cosimo Pinto, Roopesh Anand, Petr Cejka
DNA end resection initiates the largely accurate repair of DNA double-strand breaks (DSBs) by homologous recombination. Specifically, recombination requires the formation of 3' overhangs at DSB sites, which is carried out by nucleases that specifically degrade 5'-terminated DNA. In most cases, DNA end resection is a two-step process, comprising of initial short-range followed by more processive long-range resection. In this chapter, we describe selected assays that reconstitute both the short- and long-range pathways...
2018: Methods in Enzymology
Roopesh Anand, Cosimo Pinto, Petr Cejka
Accurate repair of DNA double-strand breaks (DSBs) is carried out by homologous recombination. In order to repair DNA breaks by the recombination pathway, the 5'-terminated DNA strand at DSB sites must be first nucleolytically processed to produce 3'-overhang. The process is termed DNA end resection and involves the interplay of several nuclease complexes. DNA end resection commits DSB repair to the recombination pathway including a process termed single-strand annealing, as resected DNA ends are generally nonligatable by the competing nonhomologous end-joining machinery...
2018: Methods in Enzymology
Tibebe A Teklemariam, Osvaldo D Rivera, Scott W Nelson
Bacteriophage T4 encodes orthologs of the proteins Rad50 (gp46) and Mre11 (gp47), which form a heterotetrameric complex (MR) that is responsible for host genome degradation and the processing of DNA ends for recombination-dependent DNA repair. In this chapter, we describe the ensemble methods currently employed by our laboratory to characterize the exonuclease activity of the T4 MR complex. DNA exonucleases play a vital role in maintaining the integrity of DNA through their participation in DNA repair pathways and as proofreaders for DNA polymerases...
2018: Methods in Enzymology
Warayutt Pilap, Sudarat Thanonkeo, Preekamol Klanrit, Pornthap Thanonkeo
In this work, the newly isolated thermotolerant Kluyveromyces marxianus DBKKUY-103 exhibited a high ethanol fermentation efficiency at high temperatures using sweet sorghum juice (SSJ). The highest ethanol concentrations and productivities achieved under the optimum conditions using thermotolerant K. marxianus DBKKUY-103 were 85.16 g/l and 1.42 g/l.h at 37 °C and 83.46 g/l and 1.39 g/l.h at 40 °C, respectively. The expression levels of genes during ethanol fermentation at 40 °C were evaluated and the results found that the transcriptional levels of the RAD10 , RAD14 , RAD33 , RAD50 , ATPH , ATP4 , ATP16 , and ATP20 genes were up-regulated compared with those at 30 °C, suggesting that the high growth and high ethanol production efficiencies of K...
February 2018: 3 Biotech
Raneem Habib, Heidemarie Neitzel, Aurelie Ernst, John K L Wong, Bozenna Goryluk-Kozakiewicz, Antje Gerlach, Ilja Demuth, Karl Sperling, Krystyna Chrzanowska
Background: Nijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in the repair of DNA double strand breaks (DSBs), and plays a critical role in the processing of DSBs in immune gene rearrangements, telomere maintenance, and meiotic recombination. NBS skin fibroblasts grow slowly in culture and enter early into senescence...
2018: Molecular Cytogenetics
Brenda R Lemos, Adam C Kaplan, Ji Eun Bae, Alexander E Ferrazzoli, James Kuo, Ranjith P Anand, David P Waterman, James E Haber
Harnessing CRISPR-Cas9 technology provides an unprecedented ability to modify genomic loci via DNA double-strand break (DSB) induction and repair. We analyzed nonhomologous end-joining (NHEJ) repair induced by Cas9 in budding yeast and found that the orientation of binding of Cas9 and its guide RNA (gRNA) profoundly influences the pattern of insertion/deletions (indels) at the site of cleavage. A common indel created by Cas9 is a 1-bp (+1) insertion that appears to result from Cas9 creating a 1-nt 5' overhang that is filled in by a DNA polymerase and ligated...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jung-Kuei Chen, Wen-Ling Lin, Zhang Chen, Hung-Wen Liu
Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Corinne Cassani, Elisa Gobbini, Jacopo Vertemara, Weibin Wang, Antonio Marsella, Patrick Sung, Renata Tisi, Giuseppe Zampella, Maria Pia Longhese
Sae2 cooperates with the Mre11-Rad50-Xrs2 (MRX) complex to initiate resection of DNA double-strand breaks (DSBs) and to maintain the DSB ends in close proximity to allow their repair. How these diverse MRX-Sae2 functions contribute to DNA damage resistance is not known. Here, we describe mre11 alleles that suppress the hypersensitivity of sae2Δ cells to genotoxic agents. By assessing the impact of these mutations at the cellular and structural levels, we found that all the mre11 alleles that restore sae2Δ resistance to both camptothecin and phleomycin affect the Mre11 N-terminus and suppress the resection defect of sae2Δ cells by lowering MRX and Tel1 association to DSBs...
February 6, 2018: Nucleic Acids Research
Mohd Aizat Abdul Rahim, Zubaidah Haji Abdul Rahim, Wan Azman Wan Ahmad, Marina Mohd Bakri, Muhammad Dzafir Ismail, Onn Haji Hashim
An early intervention using biomarkers to predict acute myocardial infarction (AMI) will effectively reduce global heart attack incidence, particularly among high-risk patients with type 2 diabetes mellitus (T2DM). This study attempted to identify potential biomarkers by detecting changes in the levels of plasma proteins in T2DM patients following onset of AMI in comparison with those without AMI. Volunteer T2DM patients without AMI (control; n=10) and T2DM patients with AMI (n=10) were recruited. Plasma samples from these patients were evaluated via two-dimensional gel electrophoresis (2DE) to screen for proteins with level changes between the two groups...
February 8, 2018: Acta Pharmacologica Sinica
Yanling Wang, Haineng Xu, Tianrun Liu, Menggui Huang, Param-Puneet Butter, Chunsheng Li, Lin Zhang, Gary D Kao, Yanqing Gong, Amit Maity, Constantinos Koumenis, Yi Fan
Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA-PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance...
February 8, 2018: JCI Insight
Roy Kessous, David Octeau, Kathleen Klein, Patricia N Tonin, Celia M T Greenwood, Manuela Pelmus, Ido Laskov, Liron Kogan, Shannon Salvador, Susie Lau, Amber Yasmeen, Walter H Gotlieb
OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41)...
January 29, 2018: Gynecologic Oncology
Qun Tang, Yan-Ping Liu, Hai-Huan Shan, Li-Fei Tian, Jie-Zhong Zhang, Xiao-Xue Yan
RecF is a principal member of the RecF pathway. It interacts with RecO and RecR to initiate homologous recombination by loading RecA recombinases on single-stranded DNA and displacing single-stranded DNA-binding proteins. As an ATP-binding cassette ATPase, RecF exhibits ATP-dependent dimerization and structural homology with Rad50 and SMC proteins. However, the mechanism and action pattern of RecF ATP-dependent dimerization remains unclear. Here, We determined three crystal structures of TTERecF, TTERecF-ATP and TTERecF-ATPɤS from Thermoanaerobacter tengcongensis that reveal a novel ATP-driven RecF dimerization...
February 1, 2018: Scientific Reports
Zachary K Boswell, Samiur Rahman, Marella D Canny, Michael P Latham
The Mre11-Rad50 protein complex is an initial responder to sites of DNA double strand breaks. Many studies have shown that ATP binding to Rad50 causes global changes to the Mre11-Rad50 structure, which are important for DNA repair functions. Here we used methyl-based NMR spectroscopy on a series of mutants to describe a dynamic allosteric pathway within Rad50. Mutations result in changes in the side chain methyl group chemical environment that are correlated with altered nanosecond timescale dynamics. We also observe striking relationships between the magnitude of chemical shift perturbations and Rad50 and Mre11 activities...
January 26, 2018: Scientific Reports
Rabbia Tariq Khan, Ayesha Siddique, Naeem Shahid, Samina Khokher, Warda Fatima
BACKGROUND: Variants of DNA repair genes are extensively reported to cause genetic instability and increase the risk of breast cancer. In combination with NBS1, MRE11 and RAD50 constitute an MRN (MRE11-RAD50-NBS1) complex that repairs DNA damage. However, certain genetic alterations in MRE11 and RAD50 produce abnormal protein that affects the repairing process and may result in malignancy. We aimed to investigate the association of MRE11 and RAD50 polymorphisms with breast risk in the female population of Punjab, Pakistan...
January 24, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
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