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https://www.readbyqxmd.com/read/29786079/dissection-of-dna-double-strand-break-repair-using-novel-single-molecule-forceps
#1
Jing L Wang, Camille Duboc, Qian Wu, Takashi Ochi, Shikang Liang, Susan E Tsutakawa, Susan P Lees-Miller, Marc Nadal, John A Tainer, Tom L Blundell, Terence R Strick
Repairing DNA double-strand breaks (DSBs) by nonhomologous end joining (NHEJ) requires multiple proteins to recognize and bind DNA ends, process them for compatibility, and ligate them together. We constructed novel DNA substrates for single-molecule nanomanipulation, allowing us to mechanically detect, probe, and rupture in real-time DSB synapsis by specific human NHEJ components. DNA-PKcs and Ku allow DNA end synapsis on the 100 ms timescale, and the addition of PAXX extends this lifetime to ~2 s. Further addition of XRCC4, XLF and ligase IV results in minute-scale synapsis and leads to robust repair of both strands of the nanomanipulated DNA...
May 21, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29739874/pten-regulates-non-homologous-end-joining-by-epigenetic-induction-of-nhej1-xlf
#2
Parker L Sulkowski, Susan E Scanlon, Sebastian Oeck, Peter M Glazer
DNA double-strand breaks (DSBs) are the most cytotoxic DNA lesions, and up to 90% of DSBs require repair by non-homologous end joining (NHEJ). Functional and genomic analyses of patient-derived melanomas revealed that PTEN loss is associated with NHEJ deficiency. In PTEN-null melanomas PTEN complementation rescued the NHEJ defect; conversely suppression of PTEN compromised NHEJ. Mechanistic studies revealed that PTEN promotes NHEJ through direct induction of expression of XRCC4-like factor (NHEJ1/XLF) which functions in DNA end bridging and ligation...
May 8, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29522271/inhibition-of-pc4-radiosensitizes-non-small-cell-lung-cancer-by-transcriptionally-suppressing-xlf
#3
Tian Zhang, Xiaojie Liu, Xiuli Chen, Jing Wang, Yuwen Wang, Dong Qian, Qingsong Pang, Ping Wang
Positive cofactor 4 (PC4) participates in DNA damage repair and involved in nonhomologous end joining (NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4-like factor (XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non-small cell lung cancer (NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4-knockdown NSCLC cells...
April 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29511621/robust-dna-repair-in-paxx-deficient-mammalian-cells
#4
Alisa Dewan, Mengtan Xing, Marie Benner Lundbæk, Raquel Gago-Fuentes, Carole Beck, Per Arne Aas, Nina-Beate Liabakk, Siri Sæterstad, Khac Thanh Phong Chau, Bodil Merete Kavli, Valentyn Oksenych
To ensure genome stability, mammalian cells employ several DNA repair pathways. Nonhomologous DNA end joining (NHEJ) is the DNA repair process that fixes double-strand breaks throughout the cell cycle. NHEJ is involved in the development of B and T lymphocytes through its function in V(D)J recombination and class switch recombination (CSR). NHEJ consists of several core and accessory factors, including Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, Artemis, and XLF. Paralog of XRCC4 and XLF (PAXX) is the recently described accessory NHEJ factor that structurally resembles XRCC4 and XLF and interacts with Ku70/Ku80...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29511619/normal-development-of-mice-lacking-paxx-the-paralogue-of-xrcc4-and-xlf
#5
Raquel Gago-Fuentes, Mengtan Xing, Siri Sæterstad, Antonio Sarno, Alisa Dewan, Carole Beck, Stefano Bradamante, Magnar Bjørås, Valentyn Oksenych
DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29247009/nonhomologous-dna-end-joining-for-repair-of-dna-double-strand-breaks
#6
Nicholas R Pannunzio, Go Watanabe, Michael R Lieber
Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases.  NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol μ and Pol λ), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex).  Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB...
December 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29144403/the-non-homologous-end-joining-protein-paxx-acts-to-restrict-hsv-1-infection
#7
Ben J Trigg, Katharina B Lauer, Paula Fernandes Dos Santos, Heather Coleman, Gabriel Balmus, Daniel S Mansur, Brian J Ferguson
Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection...
November 16, 2017: Viruses
https://www.readbyqxmd.com/read/29078113/tdp1-is-required-for-efficient-non-homologous-end-joining-in-human-cells
#8
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29077092/paxx-and-xlf-interplay-revealed-by-impaired-cns-development-and-immunodeficiency-of-double-ko-mice
#9
Vincent Abramowski, Olivier Etienne, Ramy Elsaid, Junjie Yang, Aurélie Berland, Laetitia Kermasson, Benoit Roch, Stefania Musilli, Jean-Paul Moussu, Karelia Lipson-Ruffert, Patrick Revy, Ana Cumano, François D Boussin, Jean-Pierre de Villartay
The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions...
February 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28930678/dna-ligase-iv-guides-end-processing-choice-during-nonhomologous-end-joining
#10
Michael P Conlin, Dylan A Reid, George W Small, Howard H Chang, Go Watanabe, Michael R Lieber, Dale A Ramsden, Eli Rothenberg
Nonhomologous end joining (NHEJ) must adapt to diverse end structures during repair of chromosome breaks. Here, we investigate the mechanistic basis for this flexibility. DNA ends are aligned in a paired-end complex (PEC) by Ku, XLF, XRCC4, and DNA ligase IV (LIG4); we show by single-molecule analysis how terminal mispairs lead to mobilization of ends within PECs and consequent sampling of more end-alignment configurations. This remodeling is essential for direct ligation of damaged and mispaired ends during cellular NHEJ, since remodeling and ligation of such ends both require a LIG4-specific structural motif, insert1...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28846869/xlf-cernunnos-an-important-but-puzzling-participant-in-the-nonhomologous-end-joining-dna-repair-pathway
#11
REVIEW
Vijay Menon, Lawrence F Povirk
DNA double strand breaks (DSBs) are one of the most deleterious DNA lesions that promote cell death, genomic instability and carcinogenesis. The two major cellular mechanisms that repair DSBs are Nonhomologous End-Joining (NHEJ) and Homologous Recombination Repair (HRR). NHEJ is the predominant pathway, in which XLF (also called Cernunnos) is a key player. Patients with XLF mutation exhibit microcephaly, lymphopenia, and growth retardation, and are immunodeficient and radiosensitive. During NHEJ, XLF interacts with XRCC4-Ligase IV, stimulates its ligase activity, and forms DNA-binding filaments of alternating XLF and XRCC4 dimers that may serve to align broken DNA and promote ligation of noncomplementary ends...
October 2017: DNA Repair
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#12
Mengtan Xing, Magnar Bjørås, Jeremy A Daniel, Frederick W Alt, Valentyn Oksenych
DNA double-strand breaks (DSBs) are recognized and repaired by the Classical Non-Homologous End-Joining (C-NHEJ) and Homologous Recombination pathways. C-NHEJ includes the core Ku70 and Ku80 (or Ku86) heterodimer that binds DSBs and thus promotes recruitment of accessory downstream NHEJ factors XLF, PAXX, DNA-PKcs, Artemis and other core subunits, XRCC4 and DNA Ligase 4 (Lig4). In the absence of core C-NHEJ factors, DNA repair can be performed by Alternative End-Joining, which likely depends on DNA Ligase 1 and DNA Ligase 3...
September 2017: DNA Repair
https://www.readbyqxmd.com/read/28645371/ensemble-and-single-molecule-analysis-of-non-homologous-end-joining-in-frog-egg-extracts
#13
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
#14
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
#15
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/28444538/occurrence-and-genetic-diversity-analysis-of-apple-stem-pitting-virus-isolated-from-apples-in-china
#16
Guo-Jun Hu, Ya-Feng Dong, Zun-Ping Zhang, Xu-Dong Fan, Fang Ren, Zhengnan Li
Two primer pairs were used to detect apple stem pitting virus (ASPV) using a reverse transcription (RT)-PCR test. 82 out of the 141 randomly collected samples, from ten orchards in five provinces and regions of China, tested positive. In the positive samples forty-five (55%) were infected by ASPV and two other viruses. The full coat protein (CP) and the triple gene block (TGB) gene 1, 2 and 3 of partial ASPV isolates were subsequently cloned. The nucleotide and amino acid identities of 39 CP sequence variants from 31 Chinese apple samples were compared with that of previously reported ASPV isolates and were 67...
August 2017: Archives of Virology
https://www.readbyqxmd.com/read/28426349/rna-binding-protein-rbm14-regulates-dissociation-and-association-of-non-homologous-end-joining-proteins
#17
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...
June 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28392333/outcome-of-hematopoietic-cell-transplantation-for-dna-double-strand-break-repair-disorders
#18
James Slack, Michael H Albert, Dmitry Balashov, Bernd H Belohradsky, Alice Bertaina, Jack Bleesing, Claire Booth, Jochen Buechner, Rebecca H Buckley, Marie Ouachée-Chardin, Elena Deripapa, Katarzyna Drabko, Mary Eapen, Tobias Feuchtinger, Andrea Finocchi, H Bobby Gaspar, Sujal Ghosh, Alfred Gillio, Luis I Gonzalez-Granado, Eyal Grunebaum, Tayfun Güngör, Carsten Heilmann, Merja Helminen, Kohei Higuchi, Kohsuke Imai, Krzysztof Kalwak, Nubuo Kanazawa, Gülsün Karasu, Zeynep Y Kucuk, Alexandra Laberko, Andrzej Lange, Nizar Mahlaoui, Roland Meisel, D Moshous, Hideki Muramatsu, Suhag Parikh, Srdjan Pasic, Irene Schmid, Catharina Schuetz, Ansgar Schulz, Kirk R Schultz, Peter J Shaw, Mary A Slatter, Karl-Walter Sykora, Shinobu Tamura, Mervi Taskinen, Angela Wawer, Beata Wolska-Kuśnierz, Morton J Cowan, Alain Fischer, Andrew R Gennery
BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed...
January 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28382333/slow-magnetic-relaxations-in-a-ladder-type-dy-iii-complex-and-its-dinuclear-analogue
#19
R Boča, M Stolárová, L R Falvello, M Tomás, J Titiš, J Černák
The complex {[Dy2 (PDOA)3 (H2 O)6 ]·2H2 O}n (1) (H2 PDOA = 1,2-phenylenedioxydiacetic acid) was prepared from aqueous solution. Its crystal structure, built up of {-Dy-O-C-O-}n chains interlinked by PDOA ligands yielding a ladder-like arrangement, was determined at 173 K. 1 exhibits slow magnetic relaxation under a small magnetic field BDC = 0.2 T with two (LF and HF) relaxation channels. The LF relaxation time at BDC = 0.2 T and T = 1.85 K is as slow as τ(LF) = 46 ms whereas the HF channel is τ(HF) = 1...
April 19, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28369633/mutations-in-xlf-nhej1-cernunnos-gene-results-in-downregulation-of-telomerase-genes-expression-and-telomere-shortening
#20
Jaime Carrillo, Oriol Calvete, Laura Pintado-Berninches, Cristina Manguan-García, Julian Sevilla Navarro, Elena G Arias-Salgado, Leandro Sastre, Guillermo Guenechea, Eduardo López Granados, Jean-Pierre de Villartay, Patrick Revy, Javier Benitez, Rosario Perona
NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells...
May 15, 2017: Human Molecular Genetics
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