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https://www.readbyqxmd.com/read/27924031/ubiquitylation-dependent-regulation-of-neil1-by-mule-and-trim26-is-required-for-the-cellular-dna-damage-response
#1
Matthew J Edmonds, Rachel J Carter, Catherine M Nickson, Sarah C Williams, Jason L Parsons
Endonuclease VIII-like protein 1 (NEIL1) is a DNA glycosylase involved in initiating the base excision repair pathway, the major cellular mechanism for repairing DNA base damage. Here, we have purified the major E3 ubiquitin ligases from human cells responsible for regulation of NEIL1 by ubiquitylation. Interestingly, we have identified two enzymes that catalyse NEIL1 polyubiquitylation, Mcl-1 ubiquitin ligase E3 (Mule) and tripartite motif 26 (TRIM26). We demonstrate that these enzymes are capable of polyubiquitylating NEIL1 in vitro, and that both catalyse ubiquitylation of NEIL1 within the same C-terminal lysine residues...
October 18, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27924007/bridging-of-double-stranded-breaks-by-the-nonhomologous-end-joining-ligation-complex-is-modulated-by-dna-end-chemistry
#2
Dylan A Reid, Michael P Conlin, Yandong Yin, Howard H Chang, Go Watanabe, Michael R Lieber, Dale A Ramsden, Eli Rothenberg
The nonhomologous end-joining (NHEJ) pathway is the primary repair pathway for DNA double strand breaks (DSBs) in humans. Repair is mediated by a core complex of NHEJ factors that includes a ligase (DNA Ligase IV; L4) that relies on juxtaposition of 3' hydroxyl and 5' phosphate termini of the strand breaks for catalysis. However, chromosome breaks arising from biological sources often have different end chemistries, and how these different end chemistries impact the way in which the core complex directs the necessary transitions from end pairing to ligation is not known...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923671/a-core-component-of-the-cul4-ubiquitin-ligase-complexes-ddb1-regulates-spermatogenesis-in-the-chinese-mitten-crab-eriocheir-sinensis
#3
AnYu Fang, XueJie Li, YuanLi Wang, DiYue Pan, Qun Wang
Studies in mammals have shown that damaged DNA-binding protein 1 (DDB1) is a multifunctional protein that recognizes UV-induced DNA lesions and activates nucleotide excision repair process, and could also be a linker protein for Cullin4 in ubiquitination to regulate cell cycle progression. However, there are few studies of DBB1 in crustaceans. In this study, a cDNA representing the DDB1 gene from Eriocheir sinensis (Es-DDB1) was cloned successfully. The full length Es-DDB1 cDNA comprises 4871 nucleotides, and encodes an open-reading frame (ORF) of 1137 amino acid residues...
December 3, 2016: Gene
https://www.readbyqxmd.com/read/27915381/regulation-of-non-homologous-end-joining-via-post-translational-modifications-of-components-of-the-ligation-step
#4
REVIEW
Kristína Durdíková, Miroslav Chovanec
DNA double-strand breaks are the most serious type of DNA damage and non-homologous end joining (NHEJ) is an important pathway for their repair. In Saccharomyces cerevisiae, three complexes mediate the canonical NHEJ pathway, Ku (Ku70/Ku80), MRX (Mre11/Rad50/Xrs2) and DNA ligase IV (Dnl4/Lif1). Mammalian NHEJ is more complex, primarily as a consequence of the fact that more factors are involved in the process, and also because higher chromatin organization and more complex regulatory networks exist in mammals...
December 3, 2016: Current Genetics
https://www.readbyqxmd.com/read/27913098/succinyl-coa-synthetase-sucla2-deficiency-in-two-siblings-with-impaired-activity-of-other-mitochondrial-oxidative-enzymes-in-skeletal-muscle-without-mitochondrial-dna-depletion
#5
Xiaoping Huang, Jirair K Bedoyan, Didem Demirbas, David J Harris, Alexander Miron, Simone Edelheit, George Grahame, Suzanne D DeBrosse, Lee-Jun Wong, Charles L Hoppel, Douglas S Kerr, Irina Anselm, Gerard T Berry
Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype...
November 12, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#6
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27906959/pcna-dependent-cleavage-and-degradation-of-sde2-regulates-response-to-replication-stress
#7
Ukhyun Jo, Winson Cai, Jingming Wang, Yoojin Kwon, Alan D D'Andrea, Hyungjin Kim
Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27903963/cdh1-regulates-e2f1-degradation-in-response-to-differentiation-signals-in-keratinocytes
#8
Randeep K Singh, Lina Dagnino
The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27899652/production-of-dna-minicircles-less-than-250-base-pairs-through-a-novel-concentrated-dna-circularization-assay-enabling-minicircle-design-with-nf-%C3%AE%C2%BAb-inhibition-activity
#9
Thomas Thibault, Jeril Degrouard, Patrick Baril, Chantal Pichon, Patrick Midoux, Jean-Marc Malinge
Double-stranded DNA minicircles of less than 1000 bp in length have great interest in both fundamental research and therapeutic applications. Although minicircles have shown promising activity in gene therapy thanks to their good biostability and better intracellular trafficking, minicircles down to 250 bp in size have not yet been investigated from the test tube to the cell for lack of an efficient production method. Herein, we report a novel versatile plasmid-free method for the production of DNA minicircles comprising fewer than 250 bp...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27895153/ubiquitylation-of-ku80-by-rnf126-promotes-completion-of-nhej-mediated-dna-repair
#10
Noriko Ishida, Tadashi Nakagawa, Shun-Ichiro Iemura, Akira Yasui, Hiroki Shima, Yasutake Katoh, Yuko Nagasawa, Toru Natsume, Kazuhiko Igarashi, Keiko Nakayama
Repair of damaged DNA is critical for maintenance of genetic information. In eukaryotes, DNA double-strand breaks (DSBs) are recognized by the Ku70-Ku80 heterodimer, which then recruits proteins that mediate repair by nonhomologous end-joining (NHEJ). Prolonged retention of Ku70/80 at DSBs prevents completion of repair, however, with ubiquitylation of Ku80 having been implicated in Ku70/80 dissociation from DNA. Here we identify RNF126 as a ubiquitin ligase that is recruited to DSBs and ubiquitylates Ku80, with UBE2D3 serving as an E2...
November 28, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27895092/characterization-of-runella-slithyformis-hd-pnk-a-bifunctional-dna-rna-end-healing-enzyme-composed-of-an-n-terminal-2-3-phosphoesterase-hd-domain-and-a-c-terminal-5-oh-polynucleotide-kinase-domain
#11
Annum Munir, Stewart Shuman
: 5' and 3' end healing are key steps in nucleic acid break repair in which 5' -OH ends are phosphorylated by a polynucleotide kinase and 3' -PO4 or 2',3' -cyclic-PO4 ends are hydrolyzed by a phosphoesterase to generate the 5' -PO4 and 3' -OH termini required for sealing by classic polynucleotide ligases. End healing and sealing enzymes are present in diverse bacterial taxa, often organized as modular units within a single multifunctional polypeptide or as subunits of a repair complex...
November 28, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27887868/reassessing-apobec3g-inhibition-by-hiv-1-vif-derived-peptides
#12
Christopher M Richards, Ming Li, Angela L Perkins, Anurag Rathore, Daniel A Harki, Reuben S Harris
The human APOBEC3G (A3G) enzyme restricts HIV-1 in the absence of the viral accessory protein viral infectivity factor (Vif) by deaminating viral cDNA cytosines to uracils. These uracil lesions base-pair with adenines during the completion of reverse transcription and result in A3G signature G-to-A mutations in the viral genome. Vif protects HIV-1 from A3G-mediated restriction by forming an E3-ubiquitin ligase complex to polyubiquitinate A3G and trigger its degradation. Prior studies indicated that Vif may also directly block the enzymatic activity of A3G and, provocatively, that Vif-derived peptides, Vif 25-39 and Vif 105-119, are similarly inhibitory...
November 22, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27884978/estrogen-receptor-negativity-in-breast-cancer-a-cause-or-consequence
#13
Vijaya Narasihma Reddy Gajulapalli, Vijaya Lakshmi Malisetty, Suresh Kumar Chitta, Bramanandam Manavathi
Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of ERα expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate estrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable, to answer that two important approaches are considered: 1) Understanding the cellular origin of heterogeneity and ER negativity in breast cancers, and 2) characterization of molecular regulators of endocrine resistance...
November 24, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27879431/efficient-in-situ-detection-of-mrnas-using-the-chlorella-virus-dna-ligase-for-padlock-probe-ligation
#14
Nils Schneider, Matthias Meier
Padlock probes are single-stranded DNA molecules that are circularized upon hybridization to their target sequence by a DNA ligase. In the following the circulated padlock probes are amplified and detected with fluorescently labeled probes complementary to the amplification product. The hallmark of padlock probe assays is a high detection specificity gained by the ligation reaction. Concomitantly, the ligation reaction is the largest drawback for a quantitative in situ detection of mRNAs due to the low affinities of common DNA or RNA ligases to RNA-DNA duplex strands...
November 22, 2016: RNA
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
#15
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
#16
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/27865106/high-speed-biosensing-strategy-for-non-invasive-profiling-of-multiple-cancer-fusion-genes-in-urine
#17
Kevin M Koo, Eugene J H Wee, Matt Trau
Aberrant chromosal rearrangements, such as the multiple variants of TMPRSS2:ERG fusion gene mutations in prostate cancer (PCa), are promising diagnostic and prognostic biomarkers due to their specific expression in cancerous tissue only. Additionally, TMPRSS2:ERG variants are detectable in urine to provide non-invasive PCa diagnostic sampling as an attractive surrogate for needle biopsies. Therefore, rapid and simplistic assays for identifying multiple urinary TMPRSS2:ERG variants are potentially useful to aid in early cancer detection, immediate patient risk stratification, and prompt personalized treatment...
November 12, 2016: Biosensors & Bioelectronics
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
#18
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
#19
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/27835608/pc-1-works-in-conjunction-with-e3-ligase-chip-to-regulate-androgen-receptor-stability-and-activity
#20
Jian Wang, Hui Zhang, Xiaoqing Zhang, Peng Wang, Hongtao Wang, Fang Huang, Chenyan Zhou, Jianguang Zhou, Shanhu Li
The androgen receptor (AR) is not only a ligand-dependent transcription factor, but also functions as a licensing factor, a component of DNA replication, which is degraded during mitosis. Furthermore, the deregulation of AR activity is involved in the initiation of prostate cancer and contributes to castration resistant prostate cancer (CRPC). While AR degradation is known to occur primarily through a proteasome-mediated pathway, very little is known about how this process is regulated, especially in M phase...
November 9, 2016: Oncotarget
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