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Ligase IV

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https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#1
Michal Hammel, Yaping Yu, Sarvan Kumar Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF) and XRCC4 (X4)-DNA ligase IV (L4). In addition, Ku interacts with accessory factors such as Aprataxin and Polynucleotide kinase/phosphatase-Like Factor (APLF), yet how these factors interact to tether, process and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
November 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27872982/interplay-between-top1-and-mms21-nse2-mediated-sumoylation-in-stable-maintenance-of-long-chromosomes
#2
Lakshmi Mahendrawada, Ragini Rai, Deepash Kothiwal, Shikha Laloraya
Genetic information in cells is encrypted in DNA molecules forming chromosomes of varying sizes. Accurate replication and partitioning of chromosomes in the crowded cellular milieu is a complex process involving duplication, folding and movement. Longer chromosomes may be more susceptible to mis-segregation or DNA damage and there may exist specialized physiological mechanisms preventing this. Here, we present genetic evidence for such a mechanism which depends on Mms21/Nse2 mediated sumoylation and topoisomerase-1 (Top1) for maintaining stability of longer chromosomes...
November 21, 2016: Current Genetics
https://www.readbyqxmd.com/read/27855655/two-hits-in-one-whole-genome-sequencing-unveils-lig4-syndrome-and-urofacial-syndrome-in-a-case-report-of-a-child-with-complex-phenotype
#3
Abeer Fadda, Fiza Butt, Sara Tomei, Sara Deola, Bernice Lo, Amal Robay, Alya Al-Shakaki, Noor Al-Hajri, Ronald Crystal, Marios Kambouris, Ena Wang, Francesco M Marincola, Khalid A Fakhro, Chiara Cugno
BACKGROUND: Ligase IV syndrome, a hereditary disease associated with compromised DNA damage response mechanisms, and Urofacial syndrome, caused by an impairment of neural cell signaling, are both rare genetic disorders, whose reports in literature are limited. We describe the first case combining both disorders in a specific phenotype. CASE PRESENTATION: We report a case of a 7-year old girl presenting with a complex phenotype characterized by multiple congenital abnormalities and dysmorphic features, microcephaly, short stature, combined immunodeficiency and severe vesicoureteral reflux...
November 17, 2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27853172/lithium-promotes-dna-stability-and-survival-of-ischemic-retinal-neurocytes-by-upregulating-dna-ligase-iv
#4
Ying Yang, Nandan Wu, Sijia Tian, Fan Li, Huan Hu, Pei Chen, Xiaoxiao Cai, Lijun Xu, Jing Zhang, Zhao Chen, Jian Ge, Keming Yu, Jing Zhuang
Neurons display genomic fragility and show fragmented DNA in pathological degeneration. A failure to repair DNA breaks may result in cell death or apoptosis. Lithium protects retinal neurocytes following nutrient deprivation or partial nerve crush, but the underlying mechanisms are not well defined. Here we demonstrate that pretreatment with lithium protects retinal neurocytes from ischemia-induced damage and enhances light response in rat retina following ischemia-reperfusion injury. Moreover, we found that DNA nonhomologous end-joining (NHEJ) repair is implicated in this process because in ischemic retinal neurocytes, lithium significantly reduces the number of γ-H2AX foci (well-characterized markers of DNA double-strand breaks in situ) and increases the DNA ligase IV expression level...
November 17, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27852949/transcriptional-gene-silencing-maintained-by-ots1-sumo-protease-requires-a-polymerase-v-dependent-pathway
#5
Lei Liu, Xiaojing Yan, Xiang Xiong Kong, Yiqiang Zhao, Zhizhong Gong, Jing Bo Jin, Yan Guo
The expression of genes with aberrant structure is prevented at both transcriptional- and posttranscriptional-regulation levels. Aberrant gene silencing at posttranscriptional level is well studied, however, it is not well understood how aberrant genes are silenced at transcriptional level. In this study, through genetic screening a transgenic report line that harbors an aberrant gene (35S-LUC, lacking 3'-UTR) and lacks luciferase (LUC) activity, we identify that the SUMO protease OTS1 gene is required for maintaining the silence of the reporter 35S-LUC and an endogenous mutator-like element MULE-F19G14 at transcriptional level, which requires Pol V and DDR complex, but not Pol IV...
November 16, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27830975/deficiency-of-xlf-and-paxx-prevents-dna-double-strand-break-repair-by-non-homologous-end-joining-in-lymphocytes
#6
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/27798111/the-ring-finger-domain-e3-ubiquitin-ligases-brca1-and-the-rnf20-rnf40-complex-in-global-loss-of-the-chromatin-mark-histone-h2b-monoubiquitination-h2bub1-in-cell-line-models-and-primary-high-grade-serous-ovarian-cancer
#7
Kristie-Ann Dickson, Alexander J Cole, Anthony J Gill, Adele Clarkson, Gregory B Gard, Angela Chou, Catherine J Kennedy, Beric R Henderson, Sian Fereday, Nadia Traficante, Kathryn Alsop, David D Bowtell, Anna deFazio, Roderick Clifton-Bligh, Deborah J Marsh
Enzymatic factors driving cancer-associated chromatin remodelling are of increasing interest as the role of the cancer epigenome in gene expression and DNA repair processes becomes elucidated. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) is a central histone modification that functions in histone cross-talk, transcriptional elongation, DNA repair, maintaining centromeric chromatin and replication-dependent histone mRNA 3'-end processing, as well as being required for the differentiation of stem cells...
October 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27723831/the-architectural-chromatin-factor-high-mobility-group-a1-enhances-dna-ligase-iv-activity-influencing-dna-repair
#8
Ilenia Pellarin, Laura Arnoldo, Silvia Costantini, Silvia Pegoraro, Gloria Ros, Carlotta Penzo, Gianluca Triolo, Francesca Demarchi, Riccardo Sgarra, Alessandro Vindigni, Guidalberto Manfioletti
The HMGA1 architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1 is a highly connected node in the nuclear molecular network and the key aspect of HMGA1 involvement in cancer development is that HMGA1 simultaneously confers cells multiple oncogenic hits, ranging from global chromatin structural and gene expression modifications up to the direct functional alterations of key cellular proteins. Interestingly, HMGA1 also modulates DNA damage repair pathways...
2016: PloS One
https://www.readbyqxmd.com/read/27717373/dna-ligase-iv-syndrome-a-review
#9
Thomas Altmann, Andrew R Gennery
DNA ligase IV deficiency is a rare primary immunodeficiency, LIG4 syndrome, often associated with other systemic features. DNA ligase IV is part of the non-homologous end joining mechanism, required to repair DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by reactive oxygen species and ionising radiation...
October 7, 2016: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/27703001/different-dna-end-configurations-dictate-which-nhej-components-are-most-important-for-joining-efficiency
#10
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/27681131/a-tale-of-two-pmls-elements-regulating-a-differential-substrate-recognition-by-the-icp0-e3-ubiquitin-ligase-of-herpes-simplex-virus-1
#11
Yi Zheng, Subodh Kumar Samrat, Haidong Gu
: Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an α gene product required for viral replication at low multiplicities of infection. Upon entry, nuclear domain 10 (ND10) converges at the incoming DNA and represses viral gene expression. ICP0 contains a RING-type E3 ubiquitin ligase that degrades the ND10 organizer PML and disperses ND10 to alleviate the repression. In the present study, we focused on understanding the regulation of ICP0 E3 ligase activity in the degradation of different ICP0 substrates...
December 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27648936/kitenin-functions-as-a-fine-regulator-of-erbb4-expression-level-in-colorectal-cancer-via-protection-of-erbb4-from-e3-ligase-nrdp1-mediated-degradation
#12
Eun Gene Sun, Kyung Hwa Lee, Yoo-Seung Ko, Hui Jeong Choi, Jung-In Yang, Jae Hyuk Lee, Ik Joo Chung, Yun-Woong Paek, Hangun Kim, Jeong A Bae, Kyung Keun Kim
Understanding the complex biological functions of E3-ubiquitin ligases may facilitate the development of mechanism-based anti-cancer drugs. We recently identified that the KITENIN/ErbB4-Dvl2-c-Jun axis works as a novel unconventional downstream signal of epidermal growth factor (EGF) in colorectal cancer (CRC) tissues. Here we addressed whether E3-ubiquitin ligases are required for operation of this axis. We found that Nrdp1, an E3-ligase for ErbB3/ErbB4, interacted with KITENIN (KAI1 C-terminal interacting tetraspanin) to form a functional KITENIN/ErbB4/Nrdp1 complex and is responsible for down-regulating Dvl2 within this complex...
September 20, 2016: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/27626453/the-search-for-herbal-antibiotics-an-in-silico-investigation-of-antibacterial-phytochemicals
#13
Mary Snow Setzer, Javad Sharifi-Rad, William N Setzer
Recently, the emergence and spread of pathogenic bacterial resistance to many antibiotics (multidrug-resistant strains) have been increasing throughout the world. This phenomenon is of great concern and there is a need to find alternative chemotherapeutic agents to combat these antibiotic-resistant microorganisms. Higher plants may serve as a resource for new antimicrobials to replace or augment current therapeutic options. In this work, we have carried out a molecular docking study of a total of 561 antibacterial phytochemicals listed in the Dictionary of Natural Products, including 77 alkaloids (17 indole alkaloids, 27 isoquinoline alkaloids, 4 steroidal alkaloids, and 28 miscellaneous alkaloids), 99 terpenoids (5 monoterpenoids, 31 sesquiterpenoids, 52 diterpenoids, and 11 triterpenoids), 309 polyphenolics (87 flavonoids, 25 chalcones, 41 isoflavonoids, 5 neoflavonoids, 12 pterocarpans, 10 chromones, 7 condensed tannins, 11 coumarins, 30 stilbenoids, 2 lignans, 5 phenylpropanoids, 13 xanthones, 5 hydrolyzable tannins, and 56 miscellaneous phenolics), 30 quinones, and 46 miscellaneous phytochemicals, with six bacterial protein targets (peptide deformylase, DNA gyrase/topoisomerase IV, UDP-galactose mutase, protein tyrosine phosphatase, cytochrome P450 CYP121, and NAD⁺-dependent DNA ligase)...
September 12, 2016: Antibiotics
https://www.readbyqxmd.com/read/27508978/genetic-effects-of-xrcc4-and-ligase-iv-genes-on-human-glioma
#14
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
https://www.readbyqxmd.com/read/27503895/mir-579-3p-controls-melanoma-progression-and-resistance-to-target-therapy
#15
Luigi Fattore, Rita Mancini, Mario Acunzo, Giulia Romano, Alessandro Laganà, Maria Elena Pisanu, Debora Malpicci, Gabriele Madonna, Domenico Mallardo, Marilena Capone, Franco Fulciniti, Luca Mazzucchelli, Gerardo Botti, Carlo M Croce, Paolo Antonio Ascierto, Gennaro Ciliberto
Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors...
August 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27365048/chromosome-territory-relocation-during-dna-repair-requires-nuclear-myosin-1-recruitment-to-chromatin-mediated-by-%C3%AF-h2ax-signaling
#16
Mugdha Kulashreshtha, Ishita S Mehta, Pradeep Kumar, Basuthkar J Rao
During DNA damage response (DDR), certain gene rich chromosome territories (CTs) relocate to newer positions within interphase nuclei and revert to their native locations following repair. Such dynamic relocation of CTs has been observed under various cellular conditions, however, the underlying mechanistic basis of the same has remained largely elusive. In this study, we aim to understand the temporal and molecular details of such crosstalk between DDR signaling and CT relocation dynamics. We demonstrate that signaling at DNA double strand breaks (DSBs) by the phosphorylated histone variant (ϒ-H2AX) is a pre-requisite for damage induced CT relocation, as cells deficient in ϒ-H2AX signaling fail to exhibit such a response...
September 30, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27352313/response-of-vitis-vinifera-cell-cultures-to-eutypa-lata-and-trichoderma-atroviride-culture-filtrates-expression-of-defence-related-genes-and-phenotypes
#17
C Mutawila, C Stander, F Halleen, M A Vivier, L Mostert
Cell suspension cultures of Vitis vinifera cv. Dauphine berries were used to study the response to the vascular pathogen, Eutypa lata, in comparison with a biological control agent, Trichoderma atroviride, that was previously shown to be effective in pruning wound protection. The expression of genes coding for enzymes of the phenylpropanoid pathway and pathogenesis-related (PR) proteins was profiled over a 48-h period using quantitative reverse transcriptase PCR. The cell cultures responded to elicitors of both fungi with a hypersensitive-like response that lead to a decrease in cell viability...
June 28, 2016: Protoplasma
https://www.readbyqxmd.com/read/27312791/identification-and-characterization-of-novel-ligase-i-inhibitors
#18
Monica Pandey, Sujeet Kumar, Goldsmith G, Mrinal Srivastava, Santhini Elango, Mohammad Shameem, Dibyendu Bannerjee, Bibha Choudhary, Subhas S Karki, Sathees C Raghavan
The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesized putative DNA Ligase I inhibitors...
June 17, 2016: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/27303922/inhibiting-cytoplasmic-accumulation-of-hur-synergizes-genotoxic-agents-in-urothelial-carcinoma-of-the-bladder
#19
Jiawei Guo, Jing Lv, Siyu Chang, Zhi Chen, Weiqiang Lu, Chuanliang Xu, Mingyao Liu, Xiufeng Pang
HuR, an RNA-binding protein, post-transcriptionally regulates nearly 4% of encoding proteins implicated in cell survival. Here we show that HuR is required for the efficacy of chemotherapies in urothelial carcinoma of the bladder. We identify pyrvinium pamoate, an FDA-approved anthelminthic drug, as a novel HuR inhibitor that dose-dependently inhibited cytoplasmic accumulation of HuR. Combining pyrvinium pamoate with chemotherapeutic agents (e.g. cisplatin, doxorubicin, vincristine and oxaliplatin) not only led to enhanced cytotoxicity in bladder cancer cells but also synergistically suppressed the growth of patient-derived bladder tumor xenografts in mice (P < 0...
June 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27237972/tgf-%C3%AE-1-accelerates-the-dna-damage-response-in-epithelial-cells-via-smad-signaling
#20
Jeeyong Lee, Mi-Ra Kim, Hyun-Ji Kim, You Sun An, Jae Youn Yi
The evidence suggests that transforming growth factor-beta (TGF-β) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-β1 induced DNA ligase IV (Lig4) expression and enhanced the nonhomologous end-joining repair pathway in irradiated cells. In the present study, we investigated the effects of TGF-β1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-β1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (γH2AX)...
August 5, 2016: Biochemical and Biophysical Research Communications
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