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Manabu Koike, Yasutomo Yutoku, Aki Koike
Understanding the molecular mechanisms of DNA double-strand break (DSB) repair processes, especially nonhomologous DNA-end joining (NHEJ), is critical for developing next-generation radiotherapies and chemotherapeutics for human and animal cancers. The localization, protein-protein interactions and post-translational modifications of core NHEJ factors, such as human Ku70 and Ku80, might play critical roles in controlling NHEJ activity. XRCC4-like factor (XLF) is a core NHEJ factor and plays a key role in the Ku-dependent NHEJ repair process in human cells...
October 14, 2016: Journal of Veterinary Medical Science
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
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 double-stranded DNA (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)...
October 4, 2016: Journal of Biological Chemistry
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
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
Sizhe Feng, Ramin Rabii, Guobiao Liang, Chenxi Song, Wei Chen, Mian Guo, Xuezhong Wei, Diana Messadi, Shen Hu
XRCC4-like factor (XLF), also known as Cernunnos, is a protein encoded by the human NHEJ1 gene and an important repair factor for DNA double-strand breaks. In this study, we have found that XLF is over-expressed in HPV(+) versus HPV(-) head and neck squamous cell carcinoma (HNSCC) and significantly down-regulated in the HNSCC cell lines expressing high level of mutant p53 protein versus those cell lines harboring wild-type TP53 gene with low p53 protein expression. We have also demonstrated that Werner syndrome protein (WRN), a member of the NHEJ repair pathway, binds to both mutant p53 protein and NHEJ1 gene promoter, and siRNA knockdown of WRN leads to the inhibition of XLF expression in the HNSCC cells...
2016: Journal of Cancer
Jonathan L Schmid-Burgk, Klara Höning, Thomas S Ebert, Veit Hornung
The site-specific insertion of heterologous genetic material into genomes provides a powerful means to study gene function. Here we describe a modular system entitled CRISPaint (CRISPR-assisted insertion tagging) that allows precise and efficient integration of large heterologous DNA cassettes into eukaryotic genomes. CRISPaint makes use of the CRISPR-Cas9 system to introduce a double-strand break (DSB) at a user-defined genomic location. A universal donor DNA, optionally provided as minicircle DNA, is cleaved simultaneously to be integrated at the genomic DSB, while processing the donor plasmid at three possible positions allows flexible reading-frame selection...
2016: Nature Communications
Ineke Brouwer, Gerrit Sitters, Andrea Candelli, Stephanie J Heerema, Iddo Heller, Abinadabe J de Melo, Hongshan Zhang, Davide Normanno, Mauro Modesti, Erwin J G Peterman, Gijs J L Wuite
Non-homologous end joining (NHEJ) is the primary pathway for repairing DNA double-strand breaks (DSBs) in mammalian cells. Such breaks are formed, for example, during gene-segment rearrangements in the adaptive immune system or by cancer therapeutic agents. Although the core components of the NHEJ machinery are known, it has remained difficult to assess the specific roles of these components and the dynamics of bringing and holding the fragments of broken DNA together. The structurally similar XRCC4 and XLF proteins are proposed to assemble as highly dynamic filaments at (or near) DSBs...
July 28, 2016: Nature
Hanna IJspeert, Jacob Rozmus, Klaus Schwarz, René L Warren, David van Zessen, Robert A Holt, Ingrid Pico-Knijnenburg, Erik Simons, Isabel Jerchel, Angela Wawer, Myriam Lorenz, Turkan Patıroğlu, Himmet Haluk Akar, Ricardo Leite, Nicole S Verkaik, Andrew P Stubbs, Dik C van Gent, Jacques J M van Dongen, Mirjam van der Burg
Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex...
August 4, 2016: Blood
H Haluk Akar, Turkan Patiroglu, Michael Hershfield, Mirjam van der Burg
Combined immunodeficiencies (CIDs) include a group of inherited monogenic disorders. CIDs are characterized by defective cellular and humoral immunities that lead to severe infections. CIDs can be classified according to immunologic phenotypes as T(-)B(-)NK(-) CID, T(-)B(-)NK(+) CID, T(-)B(+)NK(-) CID and T(-)B(+)NK(+) CID. In a 20-year period, from 1994 to 2014, a total of 40 CID patients were diagnosed at the Pediatric Immunology of Erciyes University Medical Faculty in Kayseri, Turkey. The gender ratio (F/M) was 3/5...
2016: Central-European Journal of Immunology
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...
2016: Nature Communications
Mohammed Almohaini, Sri Lakshmi Chalasani, Duaa Bafail, Konstantin Akopiants, Tong Zhou, Steven M Yannone, Dale A Ramsden, Matthew C T Hartman, Lawrence F Povirk
DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol at the first (Tg1), second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3' terminus, was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break...
May 2016: DNA Repair
Thomas G W Graham, Johannes C Walter, Joseph J Loparo
Repair of DNA double-strand breaks (DSBs) is essential for genomic stability. The most common DSB repair mechanism in human cells, non-homologous end joining (NHEJ), rejoins broken DNA ends by direct ligation. It remains unclear how components of the NHEJ machinery assemble a synaptic complex that bridges DNA ends. Here, we use single-molecule imaging in a vertebrate cell-free extract to show that synapsis of DNA ends occurs in at least two stages that are controlled by different NHEJ factors. DNA ends are initially tethered in a long-range complex whose formation requires the Ku70/80 heterodimer and the DNA-dependent protein kinase catalytic subunit...
March 17, 2016: Molecular Cell
Chloé Lescale, Vincent Abramowski, Marie Bedora-Faure, Valentine Murigneux, Gabriella Vera, David B Roth, Patrick Revy, Jean-Pierre de Villartay, Ludovic Deriano
XRCC4-like factor (XLF) functions in classical non-homologous end-joining (cNHEJ) but is dispensable for the repair of DNA double-strand breaks (DSBs) generated during V(D)J recombination. A long-standing hypothesis proposes that, in addition to its canonical nuclease activity, the RAG1/2 proteins participate in the DNA repair phase of V(D)J recombination. Here we show that in the context of RAG2 lacking the C-terminus domain (Rag2(c/c) mice), XLF deficiency leads to a profound lymphopenia associated with a severe defect in V(D)J recombination and, in the absence of p53, increased genomic instability at V(D)J sites...
2016: Nature Communications
Emilios Gemenetzidis, Luke Gammon, Adrian Biddle, Helena Emich, Ian C Mackenzie
There is a significant amount of evidence to suggest that human tumors are driven and maintained by a sub-population of cells, known as cancer stem cells (CSC). In the case of head and neck cancer, such cells have been characterised by high expression levels of CD44 cell surface glycoprotein, while we have previously shown the presence of two diverse oral CSC populations in vitro, with different capacities for cell migration and proliferation. Here, we examined the response of oral CSC populations to ionising radiation (IR), a front-line measure for the treatment of head and neck tumors...
December 22, 2015: Oncotarget
Wenjian Gan, Pengda Liu, Wenyi Wei
To maintain genome stability, mammalian cells have developed a delicate, yet efficient, system to sense and repair damaged DNA, including two evolutionarily conserved DNA damage repair (DDR) pathways: homologous recombination (HR) and non-homologous-end-joining (NHEJ). Deregulation in these repair pathways may lead to genomic instability and subsequent human diseases, including cancer. On the other hand, hyper-activation of the oncogenic Akt signaling pathway has been observed in almost all solid tumors. Emerging evidence has begun to reveal a possible role of active Akt in regulating DDR, possibly through suppression of HR...
2015: Nucleus
Turkan Patiroglu, H Haluk Akar, Mirjam van der Burg, Olgun Kontas
No abstract text is available yet for this article.
December 2015: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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
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
Manabu Koike, Yasutomo Yutoku, Aki Koike
Clinically, many chemotherapeutics and ionizing radiation (IR) have been applied for the treatment of various types of human and animal malignancies. These treatments kill tumor cells by causing DNA double-strand breaks (DSBs). Core factors of classical nonhomologous DNA-end joining (C-NHEJ) play a vital role in DSB repair. Thus, it is indispensable to clarify the mechanisms of C-NHEJ in order to develop next-generation chemotherapeutics for cancer. The XRCC4-like factor (XLF; also called Cernunnos or NHEJ1) is the lastly identified core NHEJ factor...
September 2015: Journal of Veterinary Medical Science
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