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https://www.readbyqxmd.com/read/28645371/ensemble-and-single-molecule-analysis-of-non-homologous-end-joining-in-frog-egg-extracts
#1
Thomas G W Graham, Johannes C Walter, Joseph J Loparo
Non-homologous end joining (NHEJ) repairs the majority of DNA double-strand breaks in human cells, yet the detailed order of events in this process has remained obscure. Here, we describe how to employ Xenopus laevis egg extract for the study of NHEJ. The egg extract is easy to prepare in large quantities, and it performs efficient end joining that requires the core end joining proteins Ku, DNA-PKcs, XLF, XRCC4, and DNA ligase IV. These factors, along with the rest of the soluble proteome, are present at endogenous concentrations, allowing mechanistic analysis in a system that begins to approximate the complexity of cellular end joining...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28526069/xlf-mediated-nhej-activity-in-hepatocellular-carcinoma-therapy-resistance
#2
Sitian Yang, Xiao Qi Wang
BACKGROUND: DNA repair pathways are used by cancer cells to overcome many standard anticancer treatments, causing therapy resistance. Here, we investigated the role of XRCC4-like factor (XLF), a core member of the non-homologous end joining (NHEJ) repair pathway, in chemoresistance in hepatocellular carcinoma (HCC). METHODS: qRT-PCR analysis and western blotting were performed to detect expression levels of genes and proteins related to NHEJ. NHEJ repair capacity was assessed in vitro (cell-free) and in vivo by monitoring the activity of the NHEJ pathway...
May 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28500754/mutational-phospho-mimicry-reveals-a-regulatory-role-for-the-xrcc4-and-xlf-c-terminal-tails-in-modulating-dna-bridging-during-classical-non-homologous-end-joining
#3
Davide Normanno, Aurélie Négrel, Abinadabe J de Melo, Stéphane Betzi, Katheryn Meek, Mauro Modesti
XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM...
May 13, 2017: ELife
https://www.readbyqxmd.com/read/28453785/structural-and-functional-characterization-of-the-pnkp-xrcc4-ligiv-dna-repair-complex
#4
R Daniel Aceytuno, Cortt G Piett, Zahra Havali-Shahriari, Ross A Edwards, Martial Rey, Ruiqiong Ye, Fatima Javed, Shujuan Fang, Rajam Mani, Michael Weinfeld, Michal Hammel, John A Tainer, David C Schriemer, Susan P Lees-Miller, J N Mark Glover
Non-homologous end joining (NHEJ) repairs DNA double strand breaks in non-cycling eukaryotic cells. NHEJ relies on polynucleotide kinase/phosphatase (PNKP), which generates 5΄-phosphate/3΄-hydroxyl DNA termini that are critical for ligation by the NHEJ DNA ligase, LigIV. PNKP and LigIV require the NHEJ scaffolding protein, XRCC4. The PNKP FHA domain binds to the CK2-phosphorylated XRCC4 C-terminal tail, while LigIV uses its tandem BRCT repeats to bind the XRCC4 coiled-coil. Yet, the assembled PNKP-XRCC4-LigIV complex remains uncharacterized...
June 2, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28451577/expression-levels-of-two-dna-repair-related-genes-under-8-gy-ionizing-radiation-and-100-mg-kg-melatonin-delivery-in-rat-peripheral-blood
#5
M Valizadeh, A Shirazi, P Izadi, J Tavakkoly Bazzaz, H Rezaeejam
BACKGROUND: After radiation therapy (RT), some health hazards including DNA damages may occur where melatonin can play a protective role due to free radical generation. On the other hand, serious accidental overexposures may occur during RT due to nuclear accidents which necessitate the need for study on exposure to high-dose radiations during treatments. OBJECTIVE: The aim of this study was to study the expression level of two genes in non-homologous end joining (NHEJ) pathways named Xrcc4 and Xrcc6 (Ku70) in order to examine the effect of melatonin on repair of DNA double-strand breaks (BSBs) caused by 8Gy ionizing radiation...
March 2017: Journal of Biomedical Physics & Engineering
https://www.readbyqxmd.com/read/28426349/rna-binding-protein-rbm14-regulates-dissociation-and-association-of-non-homologous-end-joining-proteins
#6
Nicholas E Simon, Ming Yuan, Mihoko Kai
Defects in the DNA damage response (DDR) are associated with multiple diseases, including cancers and neurodegenerative disorders. Emerging evidence indicates involvement of RNA-binding proteins (RBPs) in DDR. However, functions of RBPs in the DDR pathway remain elusive. We have shown previously that the RNA-binding protein RBM14 is required for non-homologous end joining (NHEJ). Here we show that RBM14 is required for efficient recruitment of XRCC4 and XLF to chromatin and the release of KU proteins from chromatin upon DNA damage...
April 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28361061/non-homologous-end-joining-protein-expression-screen-from-radiosensitive-cancer-patients-yields-a-novel-dna-double-strand-break-repair-phenotype
#7
Michael J McKay, Su Kak Goh, Jeremy N McKay, Michael Chao, Timothy M McKay
BACKGROUND: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. METHODS: We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis...
March 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28329769/corrigendum-sliding-sleeves-of-xrcc4-xlf-bridge-dna-and-connect-fragments-of-broken-dna
#8
Ineke Brouwer, Gerrit Sitters, Andrea Candelli, Stephanie J Heerema, Iddo Heller, Abinadabe J Melo de, Hongshan Zhang, Davide Normanno, Mauro Modesti, Erwin J G Peterman, Gijs J L Wuite
No abstract text is available yet for this article.
March 30, 2017: Nature
https://www.readbyqxmd.com/read/28259963/comparison-of-the-early-response-of-human-embryonic-stem-cells-and-human-induced-pluripotent-stem-cells-to-ionizing-radiation
#9
COMPARATIVE STUDY
Wiktoria Maria Suchorska, Ewelina Augustyniak, Magdalena Łukjanow
Despite the well-demonstrated efficacy of stem cell (SC) therapy, this approach has a number of key drawbacks. One important concern is the response of pluripotent SCs to treatment with ionizing radiation (IR), given that SCs used in regenerative medicine will eventually be exposed to IR for diagnostic or treatment‑associated purposes. Therefore, the aim of the present study was to examine and compare early IR‑induced responses of pluripotent SCs to assess their radioresistance and radiosensitivity. In the present study, 3 cell lines; human embryonic SCs (hESCs), human induced pluripotent SCs (hiPSCs) and primary human dermal fibroblasts (PHDFs); were exposed to IR at doses ranging from 0 to 15 gray (Gy)...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28134666/epithelioid-trophoblastic-tumor-around-an-abdominal-cesarean-scar-a-pathologic-and-molecular-genetic-analysis
#10
Emily Han-Chung Hsiue, Chiun Hsu, Li-Hui Tseng, Tzu-Pin Lu, Kuan-Ting Kuo
Epithelioid trophoblastic tumor (ETT) is a rare chemoresistant gestational trophoblastic neoplasm that typically presents as an intrauterine lesion. To our knowledge, no isolated abdominal wall ETT around a Cesarean scar has been reported. Here we describe a 54-yr-old woman with a complex obstetric history who presented with a solitary abdominal wall tumor adjacent to the abdominal Cesarean section scar. The tumor demonstrated typical morphologic and immunophenotypic features of ETT. The gestational origin of the tumor was confirmed by microsatellite genotyping...
January 27, 2017: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/28133776/non-homologous-end-joining-common-interaction-sites-and-exchange-of-multiple-factors-in-the-dna-repair-process
#11
Stuart L Rulten, Gabrielle J Grundy
Non-homologous end-joining (NHEJ) is the dominant means of repairing chromosomal DNA double strand breaks (DSBs), and is essential in human cells. Fifteen or more proteins can be involved in the detection, signalling, synapsis, end-processing and ligation events required to repair a DSB, and must be assembled in the confined space around the DNA ends. We review here a number of interaction points between the core NHEJ components (Ku70, Ku80, DNA-PKcs, XRCC4 and Ligase IV) and accessory factors such as kinases, phosphatases, polymerases and structural proteins...
March 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28094268/contribution-of-classical-end-joining-to-pten-inactivation-in-p53-mediated-glioblastoma-formation-and-drug-resistant-survival
#12
Youn-Jung Kang, Barbara Balter, Eva Csizmadia, Brian Haas, Himanshu Sharma, Roderick Bronson, Catherine T Yan
DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking. Here we demonstrate that combined inactivation of the XRCC4 non-homologous end-joining (NHEJ) DNA repair gene and p53 efficiently induces brain tumours with hallmark characteristics of human proneural/classical glioblastoma. The murine tumours exhibit PTEN loss of function instigated by reduced PTEN mRNA, and increased phosphorylated inactivation and stability as a consequence of aberrantly elevated CK2 provoked by p53 ablation and irrevocably deregulated by NHEJ inactivation...
January 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28051062/paxx-promotes-ku-accumulation-at-dna-breaks-and-is-essential-for-end-joining-in-xlf-deficient-mice
#13
Xiangyu Liu, Zhengping Shao, Wenxia Jiang, Brian J Lee, Shan Zha
Non-homologous end-joining (NHEJ) is the most prominent DNA double strand break (DSB) repair pathway in mammalian cells. PAXX is the newest NHEJ factor, which shares structural similarity with known NHEJ factors-XRCC4 and XLF. Here we report that PAXX is dispensable for physiological NHEJ in otherwise wild-type mice. Yet Paxx(-/-) mice require XLF and Xlf(-/-) mice require PAXX for end-ligation. As such, Xlf(-/-)Paxx(-/-) mice display severe genomic instability and neuronal apoptosis, which eventually lead to embryonic lethality...
January 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28025714/bone-marrow-mesenchymal-stem-cell-transplantation-improves-radiation-induced-heart-injury-through-dna-damage-repair-in-rat-model
#14
Song Gao, Zhiying Zhao, Rong Wu, Yuecan Zeng, Zhenyong Zhang, Jianing Miao, Zhengwei Yuan
Radiotherapy is an effective form of therapy for most thoracic malignant tumors. However, myocardial injury resulting from the high doses of radiation is a severe complication. Here we aimed to study the possibility of reducing radiation-induced myocardial injury with mesenchymal stem cell (MSC) transplantation. We used MSCs extracted from bone marrow (BMSCs) to transplant via the tail vein into a radiation-induced heart injury (RIHI) rat model. The rats were divided into six groups: a Sham group, an IRR (irradiation) group, and four IRR + BMSCs transplantation groups obtained at different time points...
December 26, 2016: Radiation and Environmental Biophysics
https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#15
Michal Hammel, Yaping Yu, Sarvan K Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). Yet, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
December 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27852033/the-relationship-between-polymorphisms-of-xrcc5-genes-with-astrocytoma-prognosis-in-the-han-chinese-population
#16
Xue He, Xikai Zhu, Lei Li, Jiayi Zhang, Ruipeng Wu, Yuan Zhang, Longli Kang, Dongya Yuan, Tianbo Jin
BACKGROUND: Gliomas are highly malignant with a poor prognosis. Studies have reported that DNA repair genes influence risk for glioma, but its relationship with prognosis is unclear. In this study, we want to explore the relationship between DNA repair genes (XRCC3, XRCC4 and XRCC5) and prognosis of astrocytoma in the Chinese Han population. MATERIALS AND METHODS: 160 astrocytoma cases were recruited in our study. Survival probabilities were estimated by using Kaplan-Meier analysis, and significant differences were analyzed by using the log-rank test...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27832076/complex-breakpoints-and-template-switching-associated-with-non-canonical-termination-of-homologous-recombination-in-mammalian-cells
#17
Andrea J Hartlerode, Nicholas A Willis, Anbazhagan Rajendran, John P Manis, Ralph Scully
A proportion of homologous recombination (HR) events in mammalian cells resolve by "long tract" gene conversion, reflecting copying of several kilobases from the donor sister chromatid prior to termination. Cells lacking the major hereditary breast/ovarian cancer predisposition genes, BRCA1 or BRCA2, or certain other HR-defective cells, reveal a bias in favor of long tract gene conversion, suggesting that this aberrant HR outcome might be connected with genomic instability. If termination of gene conversion occurs in regions lacking homology with the second end of the break, the normal mechanism of HR termination by annealing (i...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27830975/deficiency-of-xlf-and-paxx-prevents-dna-double-strand-break-repair-by-non-homologous-end-joining-in-lymphocytes
#18
Putzer J Hung, Bo-Ruei Chen, Rosmy George, Caleb Liberman, Abigail J Morales, Pedro Colon-Ortiz, Jessica K Tyler, Barry P Sleckman, Andrea L Bredemeyer
Non-homologous end joining (NHEJ) is a major DNA double-strand break (DSB) repair pathway that functions in all phases of the cell cycle. NHEJ repairs genotoxic and physiological DSBs, such as those generated by ionizing radiation and during V(D)J recombination at antigen receptor loci, respectively. DNA end joining by NHEJ relies on the core factors Ku70, Ku80, XRCC4, and DNA Ligase IV. Additional proteins also play important roles in NHEJ. The XRCC4-like factor (XLF) participates in NHEJ through its interaction with XRCC4, and XLF deficiency in humans leads to immunodeficiency and increased sensitivity to ionizing radiation...
February 2017: Cell Cycle
https://www.readbyqxmd.com/read/27798842/synthetic-lethality-between-paxx-and-xlf-in-mammalian-development
#19
Gabriel Balmus, Ana C Barros, Paul W G Wijnhoven, Chloé Lescale, Hélène Lenden Hasse, Katharina Boroviak, Carlos le Sage, Brendan Doe, Anneliese O Speak, Antonella Galli, Matt Jacobsen, Ludovic Deriano, David J Adams, Andrew N Blackford, Stephen P Jackson
PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf(-/-) mice, Paxx(-/-) mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4(-/-) and Lig4(-/-) mice...
October 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27769169/unexpected-effects-of-different-genetic-backgrounds-on-identification-of-genomic-rearrangements-via-whole-genome-next-generation-sequencing
#20
Zhangguo Chen, Katherine Gowan, Sonia M Leach, Sawanee S Viboolsittiseri, Ameet K Mishra, Tanya Kadoishi, Katrina Diener, Bifeng Gao, Kenneth Jones, Jing H Wang
BACKGROUND: Whole genome next generation sequencing (NGS) is increasingly employed to detect genomic rearrangements in cancer genomes, especially in lymphoid malignancies. We recently established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells. This mouse model spontaneously develops mature B cell lymphomas (termed G1XP lymphomas). RESULTS: Here, we attempt to employ whole genome NGS to identify novel structural rearrangements, in particular inter-chromosomal translocations (CTXs), in these G1XP lymphomas...
October 21, 2016: BMC Genomics
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