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https://www.readbyqxmd.com/read/27830975/deficiency-of-xlf-and-paxx-prevents-dna-double-strand-break-repair-by-non-homologous-end-joining-in-lymphocytes
#1
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...
November 10, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27798842/synthetic-lethality-between-paxx-and-xlf-in-mammalian-development
#2
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/27705800/paxx-is-an-accessory-c-nhej-factor-that-associates-with-ku70-and-has-overlapping-functions-with-xlf
#3
Satish K Tadi, Carine Tellier-Lebègue, Clément Nemoz, Pascal Drevet, Stéphane Audebert, Sunetra Roy, Katheryn Meek, Jean-Baptiste Charbonnier, Mauro Modesti
In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a c-NHEJ core component. We report here that PAXX-deficient cells exhibit a cellular phenotype uncharacteristic of a deficiency in c-NHEJ core components. PAXX-deficient cells display normal sensitivity to radiomimetic drugs, are proficient in transient V(D)J recombination assays, and do not shift toward higher micro-homology usage in plasmid repair assays...
October 4, 2016: Cell Reports
https://www.readbyqxmd.com/read/27703001/different-dna-end-configurations-dictate-which-nhej-components-are-most-important-for-joining-efficiency
#4
Howard H Y Chang, Go Watanabe, Christina A Gerodimos, Takashi Ochi, Tom L Blundell, Stephen P Jackson, Michael R Lieber
The nonhomologous DNA end-joining (NHEJ) pathway is a key mechanism for repairing dsDNA breaks that occur often in eukaryotic cells. In the simplest model, these breaks are first recognized by Ku, which then interacts with other NHEJ proteins to improve their affinity at DNA ends. These include DNA-PKcs and Artemis for trimming the DNA ends; DNA polymerase μ and λ to add nucleotides; and the DNA ligase IV complex to ligate the ends with the additional factors, XRCC4 (X-ray repair cross-complementing protein 4), XLF (XRCC4-like factor/Cernunos), and PAXX (paralog of XRCC4 and XLF)...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27601633/paxx-and-xlf-dna-repair-factors-are-functionally-redundant-in-joining-dna-breaks-in-a-g1-arrested-progenitor-b-cell-line
#5
Vipul Kumar, Frederick W Alt, Richard L Frock
Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27601299/specific-roles-of-xrcc4-paralogs-paxx-and-xlf-during-v-d-j-recombination
#6
Chloé Lescale, Hélène Lenden Hasse, Andrew N Blackford, Gabriel Balmus, Joy J Bianchi, Wei Yu, Léa Bacoccina, Angélique Jarade, Christophe Clouin, Rohan Sivapalan, Bernardo Reina-San-Martin, Stephen P Jackson, Ludovic Deriano
Paralog of XRCC4 and XLF (PAXX) is a member of the XRCC4 superfamily and plays a role in nonhomologous end-joining (NHEJ), a DNA repair pathway critical for lymphocyte antigen receptor gene assembly. Here, we find that the functions of PAXX and XLF in V(D)J recombination are masked by redundant joining activities. Thus, combined PAXX and XLF deficiency leads to an inability to join RAG-cleaved DNA ends. Additionally, we demonstrate that PAXX function in V(D)J recombination depends on its interaction with Ku...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27063109/the-ku-binding-motif-is-a-conserved-module-for-recruitment-and-stimulation-of-non-homologous-end-joining-proteins
#7
Gabrielle J Grundy, Stuart L Rulten, Raquel Arribas-Bosacoma, Kathryn Davidson, Zuzanna Kozik, Antony W Oliver, Laurence H Pearl, Keith W Caldecott
The Ku-binding motif (KBM) is a short peptide module first identified in APLF that we now show is also present in Werner syndrome protein (WRN) and in Modulator of retrovirus infection homologue (MRI). We also identify a related but functionally distinct motif in XLF, WRN, MRI and PAXX, which we denote the XLF-like motif. We show that WRN possesses two KBMs; one at the N terminus next to the exonuclease domain and one at the C terminus next to an XLF-like motif. We reveal that the WRN C-terminal KBM and XLF-like motif function cooperatively to bind Ku complexes and that the N-terminal KBM mediates Ku-dependent stimulation of WRN exonuclease activity...
April 11, 2016: Nature Communications
https://www.readbyqxmd.com/read/26100018/xrcc4-xlf-interaction-is-variably-required-for-dna-repair-and-is-not-required-for-ligase-iv-stimulation
#8
Sunetra Roy, Abinadabe J de Melo, Yao Xu, Satish K Tadi, Aurélie Négrel, Eric Hendrickson, Mauro Modesti, Katheryn Meek
The classic nonhomologous end-joining (c-NHEJ) pathway is largely responsible for repairing double-strand breaks (DSBs) in mammalian cells. XLF stimulates the XRCC4/DNA ligase IV complex by an unknown mechanism. XLF interacts with XRCC4 to form filaments of alternating XRCC4 and XLF dimers that bridge DNA ends in vitro, providing a mechanism by which XLF might stimulate ligation. Here, we characterize two XLF mutants that do not interact with XRCC4 and cannot form filaments or bridge DNA in vitro. One mutant is fully sufficient in stimulating ligation by XRCC4/Lig4 in vitro; the other is not...
September 1, 2015: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/25987660/congenital-defects-in-v-d-j-recombination
#9
REVIEW
Jean-Pierre de Villartay
INTRODUCTION OR BACKGROUND: The V(D)J recombination is a DNA rearrangement process that generates the diversity of T and B lymphocyte immune repertoire. It proceeds through the generation of a DNA double-strand break (DNA-DSB) by the Rag1/2 lymphoid-specific factors, which is repaired by the non-homologous end joining (NHEJ) DNA repair pathway. V(D)J recombination also constitutes a checkpoint in the lymphoid development. SOURCES OF DATA: V(D)J recombination defect results in severe combined immune deficiency (SCID) with a lack of T and B lymphocytes...
June 2015: British Medical Bulletin
https://www.readbyqxmd.com/read/25670504/interactome-analysis-identifies-a-new-paralogue-of-xrcc4-in-non-homologous-end-joining-dna-repair-pathway
#10
Mengtan Xing, Mingrui Yang, Wei Huo, Feng Feng, Leizhen Wei, Wenxia Jiang, Shaokai Ning, Zhenxin Yan, Wen Li, Qingsong Wang, Mei Hou, Chunxia Dong, Rong Guo, Ge Gao, Jianguo Ji, Shan Zha, Li Lan, Huanhuan Liang, Dongyi Xu
Non-homologous end joining (NHEJ) is a major pathway to repair DNA double-strand breaks (DSBs), which can display different types of broken ends. However, it is unclear how NHEJ factors organize to repair diverse types of DNA breaks. Here, through systematic analysis of the human NHEJ factor interactome, we identify PAXX as a direct interactor of Ku. The crystal structure of PAXX is similar to those of XRCC4 and XLF. Importantly, PAXX-deficient cells are sensitive to DSB-causing agents. Moreover, epistasis analysis demonstrates that PAXX functions together with XLF in response to ionizing radiation-induced complex DSBs, whereas they function redundantly in response to Topo2 inhibitor-induced simple DSBs...
February 11, 2015: Nature Communications
https://www.readbyqxmd.com/read/25656893/the-human-paxx-protein-mediates-nonhomologous-end-joining
#11
(no author information available yet)
PAXX is a member of the XRCC4 superfamily that regulates DNA double-strand break repair via NHEJ.
February 2015: Cancer Discovery
https://www.readbyqxmd.com/read/25574025/dna-repair-paxx-a-paralog-of-xrcc4-and-xlf-interacts-with-ku-to-promote-dna-double-strand-break-repair
#12
Takashi Ochi, Andrew N Blackford, Julia Coates, Satpal Jhujh, Shahid Mehmood, Naoka Tamura, Jon Travers, Qian Wu, Viji M Draviam, Carol V Robinson, Tom L Blundell, Stephen P Jackson
XRCC4 and XLF are two structurally related proteins that function in DNA double-strand break (DSB) repair. Here, we identify human PAXX (PAralog of XRCC4 and XLF, also called C9orf142) as a new XRCC4 superfamily member and show that its crystal structure resembles that of XRCC4. PAXX interacts directly with the DSB-repair protein Ku and is recruited to DNA-damage sites in cells. Using RNA interference and CRISPR-Cas9 to generate PAXX(-/-) cells, we demonstrate that PAXX functions with XRCC4 and XLF to mediate DSB repair and cell survival in response to DSB-inducing agents...
January 9, 2015: Science
https://www.readbyqxmd.com/read/9449810/purification-and-characterization-of-a-feruloyl-esterase-from-the-fungus-penicillium-expansum
#13
J Donaghy, A M McKay
An extracellular phenolic acid esterase produced by the fungus Penicillium expansum in solid state culture released ferulic and rho-coumaric acid from methyl esters of the acids, and from the phenolic-carbohydrate esters O-[5-O-(trans-feruloyl)-alpha-L-arabinofuranosyl]-(1-->3)-O-beta- D-xylopyranosyl-(1-->4)-D-xylopyranose (FAXX) and O-[5-O-((E)-rho-coumaroyl)-alpha-L-arabinofuranosyl]- (1-->3)-O-beta-D-xylopyranosyl-(1-->4)-D-xylopyranose (PAXX). The esterase was purified 360-fold in successive steps involving ultrafiltration and column chromatography by gel filtration, anion exchange and hydrophobic interaction...
December 1997: Journal of Applied Microbiology
https://www.readbyqxmd.com/read/2285139/assay-for-trans-p-coumaroyl-esterase-using-a-specific-substrate-from-plant-cell-walls
#14
W S Borneman, R D Hartley, D S Himmelsbach, L G Ljungdahl
Cell walls of Coastal Bermuda grass (Cynodon dactylon) were treated with polysaccharide hydrolases to release O-[5-O-(trans-p-coumaroyl)-alpha-L-arabinofuranosyl]-(1----3)-O-be ta-D- xylopyranosyl-(1----4)-D-xylopyranose (PAXX) which was isolated by liquid chromatography. The isolated PAXX was greater than 95% pure as determined by 1H NMR and was used as substrate for a sensitive assay of trans-p-coumaroyl esterase. PAXX was hydrolyzed by culture filtrates from the anaerobic fungus Neocallimastix MC-2. The trans-p-coumaric acid released by enzymatic hydrolysis was assayed by reverse-phase HPLC, and as little as 100 ng of acid could be determined...
October 1990: Analytical Biochemistry
https://www.readbyqxmd.com/read/1768103/isolation-and-characterization-of-p-coumaroyl-esterase-from-the-anaerobic-fungus-neocallimastix-strain-mc-2
#15
W S Borneman, L G Ljungdahl, R D Hartley, D E Akin
An extracellular p-coumaroyl esterase produced by the anaerobic fungus Neocallimastix strain MC-2 released p-coumaroyl groups from 0-[5-0-((E)-p-coumaroyl)-alpha-L-arabinofuranosyl]-(1----3)-0-beta -D-xylopyranosyl-(1----4)-D-xylopyranose (PAXX). The esterase was purified 121-fold from culture medium in successive steps involving ultrafiltration column chromatography on S-sepharose and hydroxylapatite, isoelectric focusing, and gel filtration. The native enzyme had an apparent mass of 11 kDa under nondenaturing conditions and a mass of 5...
August 1991: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/1482195/purification-and-partial-characterization-of-two-feruloyl-esterases-from-the-anaerobic-fungus-neocallimastix-strain-mc-2
#16
W S Borneman, L G Ljungdahl, R D Hartley, D E Akin
Two extracellular feruloyl esterases (FAE-I and FAE-II) produced by the anaerobic fungus Neocallimastix strain MC-2 which cleave ferulic acid from O-(5-O-[(E)-feruloyl]-alpha-L- arabinofuranosyl)-(1-->3)-O-beta-D-xylopyranosyl-(1-->4)-D-xylopyranose (FAXX) were purified. The molecular masses of FAE-I and FAE-II were 69 and 24 kDa, respectively, under both denaturing and nondenaturing conditions. Apparent Km and maximum rate of hydrolysis with FAXX were 31.9 microM and 2.9 mumol min-1 mg-1 for FAE-I and 9...
November 1992: Applied and Environmental Microbiology
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