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NHEJ pathway

Akihisa Takahashi, Eiichiro Mori, Yosuke Nakagawa, Atsuhisa Kajihara, Tadaaki Kirita, L Pittman Douglas, Masatoshi Hasegawa, Takeo Ohnishi
PURPOSE: Heat shock induces DNA double-strand breaks (DSBs), but the precise mechanism of repairing heat-induced damage is unclear. Here, we investigated the DNA repair pathways involved in cell death induced by heat shock. MATERIALS AND METHODS: B02, a specific inhibitor of human RAD51 (homologous recombination; HR), and NU7026, a specific inhibitor of DNA-PK (non-homologous end-joining; NHEJ), were used for survival assays of human cancer cell lines with different p53-gene status...
October 24, 2016: International Journal of Hyperthermia
Jiawei Guan, Qian Zhao, Weifeng Mao
PTEN is a tumor suppressor gene characterized as a phosphatase that antagonizes the phosphatidylinositol 3-kinase signaling pathway in the cytoplasm. Nuclear PTEN plays roles in chromosomal stability, in which the double-strand breaks (DSB) repair mediated by homologous recombination (HR) and non-homologous end joining (NHEJ) is critical. Herein, the role of nuclear PTEN in DSB repair and the underlying molecular mechanism was investigated in this study. Using human breast cancer BT549 and MDA-MB-231 cell lines, we reveal a specific feature of PTEN that controls poly(ADP-ribosyl)ation of Ku70 and interferes with binding of Ku70 at DSB...
October 11, 2016: Biochimica et Biophysica Acta
Wynand Paul Roos, Andrea Krumm
Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD(+) dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair...
October 13, 2016: Nucleic Acids Research
Anirban Chakraborty, Nisha Tapryal, Tatiana Venkova, Nobuo Horikoshi, Raj K Pandita, Altaf H Sarker, Partha S Sarkar, Tej K Pandita, Tapas K Hazra
DNA double-strand breaks (DSBs) leading to loss of nucleotides in the transcribed region can be lethal. Classical non-homologous end-joining (C-NHEJ) is the dominant pathway for DSB repair (DSBR) in adult mammalian cells. Here we report that during such DSBR, mammalian C-NHEJ proteins form a multiprotein complex with RNA polymerase II and preferentially associate with the transcribed genes after DSB induction. Depletion of C-NHEJ factors significantly abrogates DSBR in transcribed but not in non-transcribed genes...
October 5, 2016: Nature Communications
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
Giulia Bastianello, Hiroshi Arakawa
All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system-gene conversion, somatic hypermutation and class switch recombination-require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease...
October 3, 2016: Nucleic Acids Research
Sylvie Moureau, Janna Luessing, Emma Christina Harte, Muriel Voisin, Noel Francis Lowndes
Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR)...
September 2016: Open Biology
Wang Wei, Wang Yushuang, Huang Lanlan, Jian Zijian, Wang Xinhua, Liu Shouren, Pi Wenhui
In animal cells, inhibition of non-homologous end joining (NHEJ) pathway improves the efficiency of homologous recombination (HR)-mediated double-strand brakes (DSBs) repair. To improve the efficiency of HR in sheep embryo fibroblasts, the NHEJ key molecule DNA ligase 4 (Lig4) was suppressed by siRNA interference. Four pairs of siRNA targeting Lig4 were designed and chemically synthesized. These siRNA were electro-transferred into sheep embryo fibroblasts respectively. Compared with the control groups, two pairs of siRNA were identified to effectively inhibit the expression of sheep Lig4 gene by qRT-PCR and Western blotting...
September 20, 2016: Yi Chuan, Hereditas
Valentina Palermo, Sara Rinalducci, Massimo Sanchez, Francesca Grillini, Joshua A Sommers, Robert M Brosh, Lello Zolla, Annapaola Franchitto, Pietro Pichierri
Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability...
2016: Nature Communications
Mert Yanik, Brigitte Müller, Fei Song, Jacqueline Gall, Franziska Wagner, Wolfgang Wende, Birgit Lorenz, Knut Stieger
In vivo genome editing represents an emerging field in the treatment of monogenic disorders, as it may constitute a solution to the current hurdles in classic gene addition therapy, which are the low levels and limited duration of transgene expression. Following the introduction of a double strand break (DSB) at the mutational site by highly specific endonucleases, such as TALENs (transcription activator like effector nucleases) or RNA based nucleases (clustered regulatory interspaced short palindromic repeats - CRISPR-Cas), the cell's own DNA repair machinery restores integrity to the DNA strand and corrects the mutant sequence, thus allowing the cell to produce protein levels as needed...
September 10, 2016: Progress in Retinal and Eye Research
Min Liu, Hongyan Wang, Solah Lee, Bailong Liu, Lihua Dong, Ya Wang
PURPOSE: To clarify which DNA double-strand break repair pathway, non-homologous end-joining (NHEJ), homologous recombination repair (HRR) or both, plays a key role in potentially lethal damage repair (PLDR). METHODS AND MATERIALS: Combining published data and our new potentially lethal damage repair (PLDR) data, we explain whether similar to sublethal damage repair (SLDR), PLDR also mainly depends on NHEJ versus HRR. The PLDR data used the same cell lines: wild type, HRR or NHEJ-deficient fibroblast cells, as those SLDR data published by our laboratory previously...
October 13, 2016: International Journal of Radiation Biology
Jun Li, Xiangbing Meng, Yuan Zong, Kunling Chen, Huawei Zhang, Jinxing Liu, Jiayang Li, Caixia Gao
Sequence-specific nucleases have been exploited to create targeted gene knockouts in various plants(1), but replacing a fragment and even obtaining gene insertions at specific loci in plant genomes remain a serious challenge. Here, we report efficient intron-mediated site-specific gene replacement and insertion approaches that generate mutations using the non-homologous end joining (NHEJ) pathway using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system...
2016: Nature Plants
Douglas G Wright, Reneau Castore, Runhua Shi, Amrita Mallick, Don G Ennis, Lynn Harrison
Mycobacterium tuberculosis and Mycobacterium smegmatis express a Ku protein and a DNA ligase D and are able to repair DNA double strand breaks (DSBs) by non-homologous end-joining (NHEJ). This pathway protects against DNA damage when bacteria are in stationary phase. Mycobacterium marinum is a member of this mycobacterium family and like M. tuberculosis is pathogenic. M. marinum lives in water, forms biofilms and infects fish and frogs. M. marinum is a biosafety level 2 (BSL2) organism as it can infect humans, although infections are limited to the skin...
September 9, 2016: Mutagenesis
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
L Hu, X Li, Q Liu, J Xu, H Ge, Z Wang, H Wang, Z Wang, C Shi, X Xu, J Huang, Z Lin, R O Pieper, C Weng
Glioblastoma multiforme (GBM) is the most common primary malignant brain cancer in adults. However, the molecular events underlying carcinogenesis and their interplay remain elusive. Here, we report that the stability of Ubiquitin-conjugating enzyme E2S (UBE2S) is regulated by the PTEN/Akt pathway and that its degradation depends on the ubiquitin-proteasome system. Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation...
September 5, 2016: Oncogene
Alasdair R Gunn, Benito Banos-Pinero, Peggy Paschke, Luis Sanchez-Pulido, Antonio Ariza, Joseph Day, Mehera Emrich, David Leys, Chris P Ponting, Ivan Ahel, Nicholas D Lakin
ADP-ribosylation by ADP-ribosyltransferases (ARTs) has a well-established role in DNA strand break repair by promoting enrichment of repair factors at damage sites through ADP-ribose interaction domains. Here, we exploit the simple eukaryote Dictyostelium to uncover a role for ADP-ribosylation in regulating DNA interstrand crosslink repair and redundancy of this pathway with non-homologous end-joining (NHEJ). In silico searches were used to identify a protein that contains a permutated macrodomain (which we call aprataxin/APLF-and-PNKP-like protein; APL)...
October 15, 2016: Journal of Cell Science
Kaja Kostyrko, Samuel Neuenschwander, Thomas Junier, Alexandre Regamey, Christian Iseli, Emanuel Schmid-Siegert, Sandra Bosshard, Stefano Majocchi, Valérie Le Fourn, Pierre-Alain Girod, Ioannis Xenarios, Nicolas Mermod
Untargeted plasmid integration into mammalian cell genomes remains a poorly understood and inefficient process. The formation of plasmid concatemers and their genomic integration has been ascribed either to non-homologous end-joining (NHEJ) or homologous recombination (HR) DNA repair pathways. However, a direct involvement of these pathways has remained unclear. Here, we show that the silencing of many HR factors enhanced plasmid concatemer formation and stable expression of the gene of interest in Chinese hamster ovary (CHO) cells, while the inhibition of NHEJ had no effect...
August 29, 2016: Biotechnology and Bioengineering
Shubhankar Suman, Santosh Kumar, Prosper N'Gouemo, Kamal Datta
Binge drinking is known to cause damage in critical areas of the brain, including the hippocampus, which is important for relational memory and is reported to be sensitive to alcohol toxicity. However, the roles of DNA double-strand break (DSB) and its repair pathways, homologous recombination (HR), and non-homologous end joining (NHEJ) in alcohol-induced hippocampal injury remain to be elucidated. The purpose of this first study was to assess alcohol-induced DNA DSB and the mechanism by which alcohol affects DSB repair pathways in rat hippocampus...
August 2016: Alcohol
Lorenza P Ferretti, Sarah-Felicitas Himmels, Anika Trenner, Christina Walker, Christine von Aesch, Aline Eggenschwiler, Olga Murina, Radoslav I Enchev, Matthias Peter, Raimundo Freire, Antonio Porro, Alessandro A Sartori
Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway...
2016: Nature Communications
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