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MRN sensor complex

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https://www.readbyqxmd.com/read/26721347/%C3%AE-lapachone-enhances-mre11-rad50-nbs1-complex-expression-in-cisplatin-induced-nephrotoxicity
#1
Tae-Won Kim, Young-Jung Kim, Hyun-Tae Kim, Se-Ra Park, Ju-Young Jung
BACKGROUND: Recent studies suggest a potential involvement of the Mre11-Rad50-Nbs1 (MRN) complex, a DNA double-strand breaks (DSBs) sensor, in the development of nephrotoxicity following cisplatin administration. β-Lapachone is a topoisomerase I inhibitor known to reduce cisplatin-induced nephrotoxicity. In this study, by assessing MRN complex expression, we explored whether β-lapachone was involved in DNA damage response in the context of cisplatin-induced nephrotoxicity. METHODS: Male Balb/c mice were randomly allocated to 4 groups: control, β-lapachone alone, cisplatin alone, and β-lapachone+cisplatin...
February 2016: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/26512707/atm-dependent-phosphorylation-of-all-three-members-of-the-mrn-complex-from-sensor-to-adaptor
#2
REVIEW
Martin F Lavin, Sergei Kozlov, Magtouf Gatei, Amanda W Kijas
The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process...
2015: Biomolecules
https://www.readbyqxmd.com/read/26280532/recruitment-and-activation-of-the-atm-kinase-in-the-absence-of-dna-damage-sensors
#3
Andrea J Hartlerode, Mary J Morgan, Yipin Wu, Jeffrey Buis, David O Ferguson
Two kinases, ATM and DNA-PKcs, control rapid responses to DNA double-strand breaks (DSBs). The paradigm for ATM control is recruitment and activation by the Mre11-Rad50-NBS1 (MRN) sensor complex, whereas DNA-PKcs requires the sensor Ku (Ku70-Ku80). Using mouse cells containing targeted mutant alleles of Mre11 (Mre11a) and/or Ku70 (Xrcc6), together with pharmacologic kinase inhibition, we demonstrate that ATM can be activated by DSBs in the absence of MRN. When MRN is deficient, DNA-PKcs efficiently substitutes for ATM in facilitating local chromatin responses...
September 2015: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/26240375/atm-dependent-phosphorylation-of-mre11-controls-extent-of-resection-during-homology-directed-repair-by-signalling-through-exonuclease-1
#4
Amanda W Kijas, Yi Chieh Lim, Emma Bolderson, Karen Cerosaletti, Magtouf Gatei, Burkhard Jakob, Frank Tobias, Gisela Taucher-Scholz, Nuri Gueven, Greg Oakley, Patrick Concannon, Ernst Wolvetang, Kum Kum Khanna, Lisa Wiesmüller, Martin F Lavin
The MRE11/RAD50/NBS1 (MRN) complex plays a central role as a sensor of DNA double strand breaks (DSB) and is responsible for the efficient activation of ataxia-telangiectasia mutated (ATM) kinase. Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival. We report here that MRE11 is also phosphorylated by ATM at S676 and S678 in response to agents that induce DNA DSB, is dependent on the presence of NBS1, and does not affect the association of members of the complex or ATM activation...
September 30, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/26068589/the-mrn-complex-is-transcriptionally-regulated-by-mycn-during-neural-cell-proliferation-to-control-replication-stress
#5
M Petroni, F Sardina, C Heil, M Sahún-Roncero, V Colicchia, V Veschi, S Albini, D Fruci, B Ricci, A Soriani, L Di Marcotullio, I Screpanti, A Gulino, G Giannini
The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells...
February 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/25903339/impact-of-the-mrn-complex-on-adeno-associated-virus-integration-and-replication-during-coinfection-with-herpes-simplex-virus-1
#6
Rachel Millet, Nelly Jolinon, Xuan-Nhi Nguyen, Gregory Berger, Andrea Cimarelli, Anna Greco, Pascale Bertrand, Margarete Odenthal, Hildegard Büning, Anna Salvetti
UNLABELLED: Adeno-associated virus (AAV) is a helper-dependent parvovirus that requires coinfection with adenovirus (AdV) or herpes simplex virus 1 (HSV-1) to replicate. In the absence of the helper virus, AAV can persist in an episomal or integrated form. Previous studies have analyzed the DNA damage response (DDR) induced upon AAV replication to understand how it controls AAV replication. In particular, it was shown that the Mre11-Rad50-Nbs1 (MRN) complex, a major player of the DDR induced by double-stranded DNA breaks and stalled replication forks, could negatively regulate AdV and AAV replication during coinfection...
July 2015: Journal of Virology
https://www.readbyqxmd.com/read/25460043/regulation-of-dna-damage-responses-and-cell-cycle-progression-by-hmob2
#7
Valenti Gomez, Ramazan Gundogdu, Marta Gomez, Lily Hoa, Neelam Panchal, Mark O'Driscoll, Alexander Hergovich
Mps one binder proteins (MOBs) are conserved regulators of essential signalling pathways. Biochemically, human MOB2 (hMOB2) can inhibit NDR kinases by competing with hMOB1 for binding to NDRs. However, biological roles of hMOB2 have remained enigmatic. Here, we describe novel functions of hMOB2 in the DNA damage response (DDR) and cell cycle regulation. hMOB2 promotes DDR signalling, cell survival and cell cycle arrest after exogenously induced DNA damage. Under normal growth conditions in the absence of exogenously induced DNA damage hMOB2 plays a role in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest...
February 2015: Cellular Signalling
https://www.readbyqxmd.com/read/25375676/combined-experimental-and-bioinformatics-analysis-for-the-prediction-and-identification-of-vhr-dusp3-nuclear-targets-related-to-dna-damage-and-repair
#8
Fabio Luis Forti
The atypical dual-specificity phosphatases (aDUSPs) are a group of protein tyrosine phosphatases (PTPs) that have been increasingly studied recently, but little is known about their substrates or their roles and regulation. aDUSPs are typically low-molecular-weight enzymes that are distinct from the mitogen-activated protein kinase phosphatases (MKPs) but that still function in the regulation of the MAPK signalling cascade. aDUSPs may also have non-MAPK substrates, based on homologies observed in the sequences flanking potential phosphotyrosine target sites of other proteins and the cell type-specific characteristics of certain aDUSPs...
January 2015: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/25320294/insight-into-the-mechanism-of-inhibition-of-adeno-associated-virus-by-the-mre11-rad50-nbs1-complex
#9
Thomas B Lentz, R Jude Samulski
UNLABELLED: Adeno-associated virus (AAV) is a dependent virus of the family Parvoviridae. The gene expression and replication of AAV and derived recombinant AAV (rAAV) vectors are severely limited (>10-fold) by the cellular DNA damage-sensing complex made up of Mre11, Rad50, and Nbs1 (MRN). The AAV genome does not encode the means to circumvent this block to productive infection but relies on coinfecting helper virus to do so. Using adenovirus helper proteins E1B55k and E4orf6, which enhance the transduction of AAV via degradation of MRN, we investigated the mechanism through which this DNA damage complex inhibits gene expression from rAAV...
January 2015: Journal of Virology
https://www.readbyqxmd.com/read/24806966/the-extent-of-error-prone-replication-restart-by-homologous-recombination-is-controlled-by-exo1-and-checkpoint-proteins
#10
Ellen Tsang, Izumi Miyabe, Ismail Iraqui, Jiping Zheng, Sarah A E Lambert, Antony M Carr
Genetic instability, a hallmark of cancer, can occur when the replication machinery encounters a barrier. The intra-S-phase checkpoint maintains stalled replication forks in a replication-competent configuration by phosphorylating replisome components and DNA repair proteins to prevent forks from catastrophically collapsing. Here, we report a novel function of the core Schizosaccharomyces pombe checkpoint sensor kinase, Rad3 (an ATR orthologue), that is independent of Chk1 and Cds1 (a CHK2 orthologue); Rad3(ATR) regulates the association of recombination factors with collapsed forks, thus limiting their genetic instability...
July 1, 2014: Journal of Cell Science
https://www.readbyqxmd.com/read/23740981/the-kinase-activity-of-ataxia-telangiectasia-mutated-interferes-with-adenovirus-e4-mutant-dna-replication
#11
Dipendra Gautam, Eileen Bridge
Adenovirus (Ad) mutants that lack early region 4 (E4) are unable to produce the early regulatory proteins that normally inactivate the Mre11/Rad50/Nbs1 (MRN) sensor complex, which is a critical component for the ability of cells to respond to DNA damage. E4 mutant infection therefore activates a DNA damage response, which in turn interferes with a productive viral infection. MRN complex proteins localize to viral DNA replication centers in E4 mutant-infected cells, and this complex is critical for activating the kinases ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR), which phosphorylate numerous substrates important for DNA repair, cell cycle checkpoint activation, and apoptosis...
August 2013: Journal of Virology
https://www.readbyqxmd.com/read/23365434/smc1-mediated-intra-s-phase-arrest-facilitates-bocavirus-dna-replication
#12
Yong Luo, Xuefeng Deng, Fang Cheng, Yi Li, Jianming Qiu
Activation of a host DNA damage response (DDR) is essential for DNA replication of minute virus of canines (MVC), a member of the genus Bocavirus of the Parvoviridae family; however, the mechanism by which DDR contributes to viral DNA replication is unknown. In the current study, we demonstrate that MVC infection triggers the intra-S-phase arrest to slow down host cellular DNA replication and to recruit cellular DNA replication factors for viral DNA replication. The intra-S-phase arrest is regulated by ATM (ataxia telangiectasia-mutated kinase) signaling in a p53-independent manner...
April 2013: Journal of Virology
https://www.readbyqxmd.com/read/22565321/cdk-targeting-of-nbs1-promotes-dna-end-resection-replication-restart-and-homologous-recombination
#13
Jacob Falck, Josep V Forment, Julia Coates, Martin Mistrik, Jiri Lukas, Jiri Bartek, Stephen P Jackson
The conserved MRE11–RAD50–NBS1 (MRN) complex is an important sensor of DNA double-strand breaks (DSBs) and facilitates DNA repair by homologous recombination (HR) and end joining. Here, we identify NBS1 as a target of cyclin-dependent kinase (CDK) phosphorylation. We show that NBS1 serine 432 phosphorylation occurs in the S, G2 and M phases of the cell cycle and requires CDK activity. This modification stimulates MRN-dependent conversion of DSBs into structures that are substrates for repair by HR. Impairment of NBS1 phosphorylation not only negatively affects DSB repair by HR, but also prevents resumption of DNA replication after replication-fork stalling...
June 2012: EMBO Reports
https://www.readbyqxmd.com/read/22464731/skp2-e3-ligase-integrates-atm-activation-and-homologous-recombination-repair-by-ubiquitinating-nbs1
#14
Juan Wu, Xian Zhang, Ling Zhang, Ching-Yuan Wu, Abdol Hossein Rezaeian, Chia-Hsin Chan, Ju-Mei Li, Jing Wang, Yuan Gao, Fei Han, Yun Seong Jeong, Xiandao Yuan, Kum Kum Khanna, Jianping Jin, Yi-Xin Zeng, Hui-Kuan Lin
The Mre11/Rad50/NBS1 (MRN) complex is thought to be a critical sensor that detects damaged DNA and recruits ATM to DNA foci for activation. However, it remains to be established how the MRN complex regulates ATM recruitment to the DNA foci during DNA double-strand breaks (DSBs). Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs. Skp2 interacts with NBS1 and triggers K63-linked ubiquitination of NBS1 upon DSBs, which is critical for the interaction of NBS1 with ATM, thereby facilitating ATM recruitment to the DNA foci for activation...
May 11, 2012: Molecular Cell
https://www.readbyqxmd.com/read/22396666/dna-damage-in-nijmegen-breakage-syndrome-cells-leads-to-parp-hyperactivation-and-increased-oxidative-stress
#15
Harald Krenzlin, Ilja Demuth, Bastian Salewsky, Petra Wessendorf, Kathrin Weidele, Alexander Bürkle, Martin Digweed
Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing...
2012: PLoS Genetics
https://www.readbyqxmd.com/read/22365830/regulation-of-dna-end-resection-by-hnrnpu-like-proteins-promotes-dna-double-strand-break-signaling-and-repair
#16
Sophie E Polo, Andrew N Blackford, J Ross Chapman, Linda Baskcomb, Serge Gravel, Andre Rusch, Anoushka Thomas, Rachel Blundred, Philippa Smith, Julia Kzhyshkowska, Thomas Dobner, A Malcolm R Taylor, Andrew S Turnell, Grant S Stewart, Roger J Grand, Stephen P Jackson
DNA double-strand break (DSB) signaling and repair are critical for cell viability, and rely on highly coordinated pathways whose molecular organization is still incompletely understood. Here, we show that heterogeneous nuclear ribonucleoprotein U-like (hnRNPUL) proteins 1 and 2 play key roles in cellular responses to DSBs. We identify human hnRNPUL1 and -2 as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN) and demonstrate that hnRNPUL1 and -2 are recruited to DNA damage in an interdependent manner that requires MRN...
February 24, 2012: Molecular Cell
https://www.readbyqxmd.com/read/22261329/dna-damage-induced-cell-death-from-specific-dna-lesions-to-the-dna-damage-response-and-apoptosis
#17
REVIEW
Wynand P Roos, Bernd Kaina
DNA damaging agents are potent inducers of cell death triggered by apoptosis. Since these agents induce a plethora of different DNA lesions, it is firstly important to identify the specific lesions responsible for initiating apoptosis before the apoptotic executing pathways can be elucidated. Here, we describe specific DNA lesions that have been identified as apoptosis triggers, their repair and the signaling provoked by them. We discuss methylating agents such as temozolomide, ionizing radiation and cisplatin, all of them are important in cancer therapy...
May 28, 2013: Cancer Letters
https://www.readbyqxmd.com/read/22210882/mre11-and-rad50-but-not-nbs1-are-essential-for-gene-targeting-in-the-moss-physcomitrella-patens
#18
Yasuko Kamisugi, Didier G Schaefer, Jaroslav Kozak, Florence Charlot, Nathalie Vrielynck, Marcela Holá, Karel J Angelis, Andrew C Cuming, Fabien Nogué
The moss Physcomitrella patens is unique among plant models for the high frequency with which targeted transgene insertion occurs via homologous recombination. Transgene integration is believed to utilize existing machinery for the detection and repair of DNA double-strand breaks (DSBs). We undertook targeted knockout of the Physcomitrella genes encoding components of the principal sensor of DNA DSBs, the MRN complex. Loss of function of PpMRE11 or PpRAD50 strongly and specifically inhibited gene targeting, whilst rates of untargeted transgene integration were relatively unaffected...
April 2012: Nucleic Acids Research
https://www.readbyqxmd.com/read/21461819/probing-the-telomere-damage-response
#19
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the inhibition of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant negative mutant TPP1(ΔRD), can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2011: Methods in Molecular Biology
https://www.readbyqxmd.com/read/20966255/atm-activation-by-oxidative-stress
#20
Zhi Guo, Sergei Kozlov, Martin F Lavin, Maria D Person, Tanya T Paull
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway...
October 22, 2010: Science
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