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homologous dependent recombination

Hao Zhang, Ning Hu
Thyroid carcinoma is the most common endocrine malignant tumor in the world, and so, there is a requirement to develop novel molecular targets for thyroid cancer diagnosis and treatment. Telomerase reverse transcriptase (TERT) was revealed to promote cell proliferation in a number of types of cell. To evaluate whether and how TERT functioned on papillary thyroid cancer (PTC) cell proliferation, the present study constructed TERT over‑expression [recombined (r)TERT plasmid group] and interference [small interfering RNA (si)‑TERT group] models by liposome transfection respectively to study the molecular mechanisms...
June 1, 2018: Molecular Medicine Reports
Atif J Khan, Sarah M Misenko, Aditya Thandoni, Devora Schiff, Sachin R Jhawar, Samuel F Bunting, Bruce G Haffty
Purpose: DNA double-strand breaks (DSBs) can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). We demonstrate the selectivity of VX-984, a DNA-PK inhibitor, using assays not previously reported. Experimental Design: The class switch recombination assay (CSR) in primary B cells was used to measure efficiency of NHEJ. A cellular reporter assay (U2OS EJ-DR) was used to assess the efficiency of HR and NHEJ in cells treated with VX-984...
May 25, 2018: Oncotarget
Michael Charles Lanz, Susannah Oberly, Ethan James Sanford, Sushma Sharma, Andrei Chabes, Marcus Bustamante Smolka
The Mec1/ATR kinase coordinates multiple cellular responses to replication stress. In addition to its canonical role in activating the checkpoint kinase Rad53, Mec1 also plays checkpoint-independent roles in genome maintenance that are not well understood. Here we used a combined genetic-phosphoproteomic approach to manipulate Mec1 activation and globally monitor Mec1 signaling, allowing us to delineate distinct checkpoint-independent modes of Mec1 action. Using cells in which endogenous Mec1 activators were genetically ablated, we found that expression of "free" Mec1 activation domains (MADs) can robustly activate Mec1 and rescue the severe DNA replication and growth defects of these cells back to wild-type levels...
June 13, 2018: Genes & Development
Chengxian Ma, Kyungsoo Ha, Min-Su Kim, Young-Woock Noh, Han Lin, Lichun Tang, Qing Zhu, Dan Zhang, Huan Chen, Suxia Han, Pumin Zhang
Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). The choice between these two pathways is largely influenced by cell cycle phases. HDR can occur only in S/G2 when sister chromatid can provide homologous templates, whereas NHEJ can take place in all phases of the cell cycle except mitosis. Central to NHEJ repair is the Ku70/80 heterodimer which forms a ring structure that binds DSB ends and serves as a platform to recruit factors involved in NHEJ...
June 12, 2018: Cell Cycle
Leslie A Parsels, Joshua D Parsels, Daria M Tanska, Jonathan Maybaum, Theodore S Lawrence, Meredith A Morgan
Small molecule inhibitors of the checkpoint proteins CHK1 and WEE1 are currently in clinical development in combination with the antimetabolite gemcitabine. It is unclear, however, if there is a therapeutic advantage to CHK1 vs. WEE1 inhibition for chemosensitization. The goals of this study were to directly compare the relative efficacies of the CHK1 inhibitor MK8776 and the WEE1 inhibitor AZD1775 to sensitize pancreatic cancer cell lines to gemcitabine and to identify pharmacodynamic biomarkers predictive of chemosensitization...
June 12, 2018: Cell Cycle
Qiqi Song, Weijiao Song, Weijing Zhang, Lan He, Rui Fang, Yanqin Zhou, Bang Shen, Min Hu, Junlong Zhao
Mycoplasma suis (M. suis) is an uncultivable haemotrophic mycoplasma that parasitizes the red blood cells of a wide range of domestic and wild animals. Adhesion of M. suis to host erythrocytes is crucial for its unique RBC-dependent lifecycle. MSG1 protein (now named as GAPDH) with homology to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was the first identified adhesion protein of M. suis. In this study, we found that O-sialoglycoprotein endopeptidase (OSGEP) is another M. suis protein capable of binding porcine erythrocytes...
May 5, 2018: Research in Veterinary Science
Sharmistha Chakraborty, Raj K Pandita, Shashank Hambarde, Abid R Mattoo, Vijaya Charaka, Kazi M Ahmed, Swaminathan P Iyer, Clayton R Hunt, Tej K Pandita
The chromatin remodeling factor SMARCAD1, an SWI/SNF ATPase family member, has a role in 5' end resection at DNA double-strand breaks (DSBs) to produce single-strand DNA (ssDNA), a critical step for subsequent checkpoint and repair factor loading to remove DNA damage. However, the mechanistic details of SMARCAD1 coupling to the DNA damage response and repair pathways remains unknown. Here we report that SMARCAD1 is recruited to DNA DSBs through an ATM-dependent process. Depletion of SMARCAD1 reduces ionizing radiation (IR)-induced repairosome foci formation and DSB repair by homologous recombination (HR)...
April 27, 2018: iScience
Marta Barrientos-Moreno, Marina Murillo-Pineda, Ana M Muñoz-Cabello, Félix Prado
Upon telomerase inactivation, telomeres gradually shorten with each cell division until cells enter replicative senescence. In Saccharomyces cerevisiae, the kinases Mec1/ATR and Tel1/ATM protect the genome during pre-senescence by preventing telomere-telomere fusions (T-TFs) and the subsequent genetic instability associated with fusion-bridge-breakage cycles. Here we report that T-TFs in mec1Δ tel1Δ cells can be suppressed by reducing the pool of available histones. This protection associates neither with changes in bulk telomere length nor with major changes in the structure of subtelomeric chromatin...
June 2018: PLoS Genetics
Ye Hong, Maria Velkova, Nicola Silva, Marlène Jagut, Viktor Scheidt, Karim Labib, Verena Jantsch, Anton Gartner
Homologous recombination is essential for crossover (CO) formation and accurate chromosome segregation during meiosis. It is of considerable importance to work out how recombination intermediates are processed, leading to CO and non-crossover (NCO) outcome. Genetic analysis in budding yeast and Caenorhabditis elegans indicates that the processing of meiotic recombination intermediates involves a combination of nucleases and DNA repair enzymes. We previously reported that in C. elegans meiotic joint molecule resolution is mediated by two redundant pathways, conferred by the SLX-1 and MUS-81 nucleases, and by the HIM-6 Bloom helicase in conjunction with the XPF-1 endonuclease, respectively...
June 7, 2018: PLoS Genetics
Larisa Y Romanova, Frederick Mushinski, Alexander L Kovalchuk
The inhibitory effect of p53 on homologous recombination (HR) is exerted through sequestration of replication protein A (RPA). Release of the p53/RPA complex in response to replication stress is crucially dependent on the phosphorylation status of both proteins and is required for efficient DNA repair by HR. Phosphorylation of RPA within its RPA2 subunit by cyclin-dependent kinases (CDK) is an early event in the replication stress response. Here we investigated the role of transcriptional activation of the p53 downstream target, p21Waf1 , on RPA2 phosphorylation, the stability of the p53/RPA complex and HR in cells undergoing replication arrest induced by camptothecin (CPT)...
May 22, 2018: Oncotarget
Maren Buss, Christina Geerds, Thomas Patschkowski, Karsten Niehaus, Hartmut H Niemann
Flavin-dependent halogenases can be used as biocatalysts because they regioselectively halogenate their substrates under mild reaction conditions. New halogenases with novel substrate specificities will add to the toolbox of enzymes available to organic chemists. HalX, the product of the xcc-b100_4193 gene, is a putative flavin-dependent halogenase from Xanthomonas campestris. The enzyme was recombinantly expressed and crystallized in order to aid in identifying its hitherto unknown substrate. Native data collected to a resolution of 2...
June 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
Iram Aziz, Tahira Bibi, Naeem Rashid, Riku Aono, Haruyuki Atomi, Muhammad Akhtar
The genome of the hyperthermophilic archaeon Pyrobaculum calidifontis contains an open reading frame Pcal_0041 annotated as PfkB family ribokinase consisting of phosphofructokinase and pyrimidine kinase domains. Among biochemically characterized enzymes, the Pcal_0041 protein was 37% identical to the phosphofructokinase (Ape_0012) from Aeropyrum pernix , which displayed kinase activity towards a broad spectrum of substrates including sugars, sugar phosphates and nucleosides, and 36% identical to a phosphofructokinase from Desulfurococcus amylolyticus In order to examine the biochemical function of the Pcal_0041 protein, we cloned and expressed the gene and purified the recombinant protein...
June 4, 2018: Journal of Bacteriology
Katrin Brockhaus, Michael R R Böhm, Harutyun Melkonyan, Solon Thanos
Increased β-synuclein (Sncb) expression has been described in the aging visual system. Sncb functions as the physiological antagonist of α-synuclein (Snca), which is involved in the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. However, the exact function of Sncb remains unknown. The aim of this study was to elucidate the age-dependent role of Sncb in brain microvascular endothelial cells (BMECs). BMECs were isolated from the cortices of 5- to 9-d-old Sprague-Dawley rats and were cultured with different concentrations of recombinant Sncb (rSncb) up to 72 h resembling to some degree age-related as well as pathophysiological conditions...
January 1, 2018: Cell Transplantation
Du Xue, Wang Guang-Hua, Su Yan-Li, Zhang Min, Hu Yong-Hua
C-type lectin (CTL) is an immune receptor and is received extensive attention of its important roles in immune response and immune escape. Some CTL, such as CTL4, has been well characterized in human and several other mammals, but much less documentation exists about the immunological function of CTL4 in lower vertebrates. In the present study, a C-type lectin domain family 4 member, SsCTL4, which is also high homology with CD209 antigen-like protein, from the teleost fish black rockfish (Sebastes schlegelii) was identified and examined at expression and functional levels...
August 2018: Fish & Shellfish Immunology
Vincent Amarh, Martin A White, David R F Leach
Chromosomal replication is the major source of spontaneous DNA double-strand breaks (DSBs) in living cells. Repair of these DSBs is essential for cell viability, and accuracy of repair is critical to avoid chromosomal rearrangements. Repair of replication-dependent DSBs occurs primarily by homologous recombination with a sister chromosome. However, this reaction has never been visualized at a defined chromosomal locus, so little is known about its spatial or temporal dynamics. Repair of a replication-independent DSB generated in Escherichia coli by a rare-cutting endonuclease leads to the formation of a bundle of RecA filaments...
May 22, 2018: Journal of Cell Biology
Emad A Ahmed, Michael Rosemann, Harry Scherthan
Exposure of cells to ionizing radiation induces DNA double-strand breaks. To repair double-strand breaks correctly, cells must distinguish between the ends of chromosomes (telomeres) and DNA double-strand breaks within chromosomes. Double-strand breaks in telomeric DNA may lead to telomere shortening and mutagenesis. Eukaryotic cells repair double-strand breaks primarily by two mechanisms: error-free homologous recombination and error-prone nonhomologous end joining, of which homologous recombination is used in early meiotic prophase I to create recombined haploid gametes by two meiotic cell divisions lacking an intervening S-phase...
July 2018: Health Physics
Kenichiro Matsuzaki, Miki Shinohara
A DNA double strand break (DSB) is one of the most cytotoxic DNA lesions, but it can be repaired by non-homologous end joining (NHEJ) or by homologous recombination. The choice between these two repair pathways depends on the cell cycle stage. Although NHEJ constitutes a simple re-ligation reaction, the regulatory mechanism(s) controlling its activity has not been fully characterized. Lif1 is a regulatory subunit of the NHEJ-specific DNA ligase IV and interacts with Xrs2 of the MRX complex which is a key factor in DSB repair...
May 17, 2018: Biochemical and Biophysical Research Communications
A Amitai, D Holcman
The time for a DNA sequence to find its homologous counterpart depends on a long random search inside the cell nucleus. Using polymer models, we compute here the mean first encounter time (MFET) between two sites located on two different polymer chains and confined locally by potential wells. We find that reducing tethering forces acting on the polymers results in local decondensation, and numerical simulations of the polymer model show that these changes are associated with a reduction of the MFET by several orders of magnitude...
March 2018: Physical Review. E
Dan N Simon, Amanda Wriston, Qiong Fan, Jeffrey Shabanowitz, Alyssa Florwick, Tejas Dharmaraj, Sherket B Peterson, Yosef Gruenbaum, Cathrine R Carlson, Line M Grønning-Wang, Donald F Hunt, Katherine L Wilson
The LMNA gene encodes lamins A and C with key roles in nuclear structure, signaling, gene regulation, and genome integrity. Mutations in LMNA cause over 12 diseases ('laminopathies'). Lamins A and C are identical for their first 566 residues. However, they form separate filaments in vivo, with apparently distinct roles. We report that lamin A is β- O -linked N -acetylglucosamine- (O -GlcNAc)-modified in human hepatoma (Huh7) cells and in mouse liver. In vitro assays with purified O -GlcNAc transferase (OGT) enzyme showed robust O -GlcNAcylation of recombinant mature lamin A tails (residues 385⁻646), with no detectable modification of lamin B1, lamin C, or 'progerin' (Δ50) tails...
May 17, 2018: Cells
Hui Wang, Zhuang Xue, Zhaoqun Liu, Weilin Wang, Feifei Wang, Ying Wang, Lingling Wang, Linsheng Song
C-type lectins (CTLs) are Ca2+ dependent carbohydrate-binding proteins that share structural homology in their carbohydrate-recognition domains (CRDs). In the present study, a novel CTL was identified from sea cucumber Apostichopus japonicus (named as AjCTL-2). The deduced amino acid sequence of AjCTL-2 was homologous to CTLs from other animals with the identities ranging from 33% to 40%. It contained a canonical signal peptide at the N-terminus, a low density lipoprotein receptor class A (LDLa), a C1r/C1s/Uegf/bone morphogenetic protein 1 (CUB), and a CRD with two motif Glu-Pro-Asn (EPN) and Trp-Asn-Asp (WND) in Ca2+ binding site 2...
May 14, 2018: Fish & Shellfish Immunology
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