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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
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
Fatemeh Sanie-Jahromi, Iraj Saadat, Mostafa Saadat
AIMS: It has been shown that exposure to extremely-low frequency (˂300Hz) oscillating electromagnetic field (EMF) can affect gene expression. The effects of different exposure patterns of 50-Hz EMF and co-treatment of EMF plus cisplatin (CDDP) on mRNA levels of seven genes involved in DNA repair pathways (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) were evaluated. MAIN METHODS: Two 50-Hz EMF intensities (0.25 and 0.50mT), three exposure patterns (5min field-on/5min field-off, 15min field-on/15min field-off, 30min field-on continuously) and two cell lines (MCF-7 and SH-SY5Y) were used...
October 6, 2016: Life Sciences
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
Magdalena B Rother, Kristin Jensen, Mirjam van der Burg, Fleur S van de Bovenkamp, Roel Kroek, Wilfred F J van IJcken, Vincent H J van der Velden, Tom Cupedo, Ole K Olstad, Jacques J M van Dongen, Menno C van Zelm
Newborns are unable to mount antibody responses towards certain antigens. This has been related to the restricted repertoire of immunoglobulin (Ig) genes of their B cells. The mechanisms underlying the restricted fetal Ig gene repertoire are currently unresolved. We here addressed this with detailed molecular and cellular analysis of human precursor-B cells from fetal liver, fetal bone marrow (BM), and pediatric BM. In the absence of selection processes, fetal B-cell progenitors more frequently used proximal V, D and J genes in complete IGH gene rearrangements, despite normal Ig locus contraction...
2016: Scientific Reports
Manabu Koike, Yasutomo Yutoku, Aki Koike
Various chemotherapies and radiation therapies are useful for killing cancer cells mainly by inducing DNA double-strand breaks (DSBs). Uncovering the molecular mechanisms of DSB repair processes is crucial for developing next-generation radiotherapies and chemotherapeutics for human and animal cancers. XRCC4 plays a critical role in Ku-dependent nonhomologous DNA-end joining (NHEJ) in human cells and is one of the core NHEJ factors. The localization of core NHEJ factors, such as human Ku70 and Ku80, might play a crucial role in regulating NHEJ activity...
September 18, 2016: Journal of Veterinary Medical Science
Maral Adel Fahmideh, Catharina Lavebratt, Joachim Schüz, Martin Röösli, Tore Tynes, Michael A Grotzer, Christoffer Johansen, Claudia E Kuehni, Birgitta Lannering, Michaela Prochazka, Lisbeth S Schmidt, Maria Feychting
Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression...
August 24, 2016: Oncotarget
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
Hanna Romanowicz, Łukasz Pyziak, Filip Jabłoński, Magdalena Bryś, Ewa Forma, Beata Smolarz
Genetic polymorphisms in the DNA repair genes may be associated with increased cancer risk. The purpose of this study was to evaluate the association of the DNA repair genes polymorphisms with the risk of breast cancer development. The study included 200 breast cancer patients and 200 healthy controls. The following polymorphisms were studied: C/G (Ser326Cys, rs1052133) of the hOGG1, A/C (IVS5 + 33, rs3212961) of the ERCC1, A/C (Lys939Gln, rs2228001) of the XPC, C/T (Thr241Met, rs861539) of the XRCC3, G/T (Leu787Leu, rs1800392) of the WRN and G/T (Ser307Ser, rs1056503) of the XRCC4 gene...
August 29, 2016: Pathology Oncology Research: POR
Yasuko Kamisugi, John W Whitaker, Andrew C Cuming
The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting...
2016: PloS One
Keping Jiao, Juan Qin, Yumei Zhao, Honglian Zhang
Ligase IV and XRCC4 genes, important molecules in the nonhomologous end-joining pathway for repairing DNA double-strand breaks, may play crucial roles in carcinogenesis. To detect their effects on the risk of human glioma, their gene expression differences between 110 human glioma tissues and 50 healthy brain tissues were determined using quantitative real-time PCR. Furthermore, two tagging single nucleotide polymorphisms (SNPs) in ligase IV and four SNPs in XRCC4 genes were genotyped in 317 glioma patients and 352 healthy controls...
September 28, 2016: Neuroreport
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
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
Z Li, W Zhang, Y Chen, W Guo, J Zhang, H Tang, Z Xu, H Zhang, Y Tao, F Wang, Y Jiang, F L Sun, Z Mao
Failing to repair DNA double-strand breaks by either nonhomologous end joining (NHEJ) or homologous recombination (HR) poses a threat to genome integrity, and may have roles in the onset of aging and age-related diseases. Recent work indicates an age-related decrease of NHEJ efficiency in mouse models, but whether NHEJ and HR change with age in humans and the underlying mechanisms of such a change remain uncharacterized. Here, using 50 eyelid fibroblast cell lines isolated from healthy donors at the age of 16-75 years, we demonstrate that the efficiency and fidelity of NHEJ, and the efficiency of HR decline with age, leading to increased IR sensitivity in cells isolated from old donors...
July 8, 2016: Cell Death and Differentiation
Masakazu Hori, Masanori Someya, Yoshihisa Matsumoto, Kensei Nakata, Mio Kitagawa, Tomokazu Hasegawa, Takaaki Tsuchiya, Yuki Fukushima, Toshio Gocho, Yasushi Sato, Hiroyuki Ohnuma, Junji Kato, Shintaro Sugita, Tadashi Hasegawa, Koh-Ichi Sakata
DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation and is mainly repaired by the non-homologous end joining (NHEJ) repair. Immunohistochemical analysis of proteins involved in NHEJ, such as XRCC4 (X-ray repair cross-complementing protein 4), Ku86 and DNA-PKcs (DNA-dependent protein kinase, catalytic subunits), may be useful for predicting tumor radiosensitivity. We examined 92 patients with esophageal squamous cell carcinoma (ECSS) who were treated by radiotherapy between 1999 and 2008...
June 23, 2016: Medical Molecular Morphology
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
Shinta Saito, Aya Kurosawa, Noritaka Adachi
In successive reports from 2014 to 2015, X-ray repair cross-complementing protein 4 (XRCC4) has been identified as a novel causative gene of primordial dwarfism. XRCC4 is indispensable for non-homologous end joining (NHEJ), the major pathway for repairing DNA double-strand breaks. As NHEJ is essential for V(D)J recombination during lymphocyte development, it is generally believed that abnormalities in XRCC4 cause severe combined immunodeficiency. Contrary to expectations, however, no overt immunodeficiency has been observed in patients with primordial dwarfism harboring XRCC4 mutations...
August 2016: Journal of Human Genetics
Angel C Y Mak, Paul L F Tang, Clare Cleveland, Melanie H Smith, M Kari Connolly, Tamiko R Katsumoto, Paul J Wolters, Pui-Yan Kwok, Lindsey A Criswell
OBJECTIVE: Scleroderma is a genetically complex autoimmune disease with substantial phenotypic heterogeneity. Previous genome-wide association studies have identified common genetic variants associated with disease risk, but these studies are not designed to capture rare or potential causal variants. Our goal was to identify rare as well as common genetic variants in patients with diffuse cutaneous systemic sclerosis (dcSSc) through whole-exome sequencing (WES) in order to identify potential causal variants...
September 2016: Arthritis & Rheumatology
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