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https://www.readbyqxmd.com/read/28334891/rad51-interconnects-between-dna-replication-dna-repair-and-immunity
#1
Souparno Bhattacharya, Kalayarasan Srinivasan, Salim Abdisalaam, Fengtao Su, Prithvi Raj, Igor Dozmorov, Ritu Mishra, Edward K Wakeland, Subroto Ghose, Shibani Mukherjee, Aroumougame Asaithamby
RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28324505/probing-the-telomere-damage-response
#2
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal 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 TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28314386/veliparib-in-combination-with-radiotherapy-for-the-treatment-of-mgmt-unmethylated-glioblastoma
#3
Toni Rose Jue, Kyoko Nozue, Ashleigh J Lester, Swapna Joshi, Lisette B W Schroder, Shane P Whittaker, Sheri Nixdorf, Robert W Rapkins, Mustafa Khasraw, Kerrie L McDonald
BACKGROUND: The O (6) -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. METHODS: The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors...
March 17, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28292918/non-homologous-end-joining-with-minimal-sequence-loss-is-promoted-by-the-mre11-rad50-nbs1-ctp1-complex-in-schizosaccharomyces-pombe
#4
Yanhui Li, Jinyu Wang, Gang Zhou, Michael Lajeunesse, Nga Le, Brittany N Stawicki, Yalitza Lopez Corcino, Kathleen L Berkner, Kurt W Runge
While the Mre11-Rad50-Nbs1 (MRN) complex has known roles in repair processes like homologous recombination and microhomology-mediated end-joining, its role in non-homologous end-joining (NHEJ) is unclear as Saccharomyces cerevisiae, Schizosaccharomyces pombe and mammals have different requirements for repairing cut DNA ends. Most double-strand breaks (DSBs) require nucleolytic processing prior to DNA ligation. We therefore studied repair using the Hermes transposon, whose excision leaves a DSB capped by hairpin ends similar to structures generated by palindromes and trinucleotide repeats...
March 14, 2017: Genetics
https://www.readbyqxmd.com/read/28261280/effect-of-irradiation-on-dna-synthesis-nbn-gene-expression-and-chromosomal-stability-in-cells-with-nbn-mutations
#5
Jerzy Nowak, Bogna Świątek-Kościelna, Ewelina M Kałużna, Jolanta Rembowska, Agnieszka Dzikiewicz-Krawczyk, Mariola Zawada, Danuta Januszkiewicz-Lewandowska
INTRODUCTION: The NBN gene product is part of the MRE11/RAD50/NBN complex, which plays an essential role in genomic stability. In the study we try to answer the question what is the effect of irradiation on DNA synthesis, NBN gene expression and chromosomal stability in cells with homozygous c.657-661del, and heterozygous c.657-661del, p.I171V and p.R215W NBN gene mutations. MATERIAL AND METHODS: Immortalized B-lymphocytes with NBN gene mutations were X-ray irradiated at doses of 1, 2, 5 and 8 Gy/min...
March 1, 2017: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/28258201/endothelial-il-33-expression-is-augmented-by-adenoviral-activation-of-the-dna-damage-machinery
#6
Tor Espen Stav-Noraas, Reidunn J Edelmann, Lars La Cour Poulsen, Olav Sundnes, Danh Phung, Axel M Küchler, Fredrik Müller, Amine A Kamen, Guttorm Haraldsen, Mari Kaarbø, Johanna Hol
IL-33, required for viral clearance by cytotoxic T cells, is generally expressed in vascular endothelial cells in healthy human tissues. We discovered that endothelial IL-33 expression was stimulated as a response to adenoviral transduction. This response was dependent on MRE11, a sensor of DNA damage that can also be activated by adenoviral DNA, and on IRF1, a transcriptional regulator of cellular responses to viral invasion and DNA damage. Accordingly, we observed that endothelial cells responded to adenoviral DNA by phosphorylation of ATM and CHK2 and that depletion or inhibition of MRE11, but not depletion of ATM, abrogated IL-33 stimulation...
March 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28216226/nbs1-phosphorylation-status-dictates-repair-choice-of-dysfunctional-telomeres
#7
Rekha Rai, Chunyi Hu, Cayla Broton, Yong Chen, Ming Lei, Sandy Chang
Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2(TRFH) domain...
February 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28178675/overexpression-of-karyopherin-a2-in-cholangiocarcinoma-correlates-with-poor-prognosis-and-gemcitabine-sensitivity-via-nuclear-translocation-of-dna-repair-proteins
#8
Mariko Tsukagoshi, Kenichiro Araki, Takehiko Yokobori, Bolag Altan, Hideki Suzuki, Norio Kubo, Akira Watanabe, Norihiro Ishii, Yasuo Hosouchi, Masahiko Nishiyama, Ken Shirabe, Hiroyuki Kuwano
Cholangiocarcinoma is a highly malignant tumor, and the development of new therapeutic strategies is critical. Karyopherin-α2 (KPNA2) functions as an adaptor that mediates nucleocytoplasmic transport. Specifically, KPNA2 transports one of the important DNA repair machineries, the MRE11-RAD50-NBS1 (MRN) complex, to the nucleus. In this study, we clarified the significance of KPNA2 in cholangiocarcinoma. KPNA2 expression evaluated by immunohistochemical analysis was common in malignant tissue but rare in adjacent noncancerous tissues...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28134932/eukaryotic-rad50-functions-as-a-rod-shaped-dimer
#9
Young Bong Park, Marcel Hohl, Michał Padjasek, Eunyoung Jeong, Kyeong Sik Jin, Artur Krężel, John H J Petrini, Yunje Cho
The Rad50 hook interface is crucial for assembly and various functions of the Mre11 complex. Previous analyses suggested that Rad50 molecules interact within (intracomplex) or between (intercomplex) dimeric complexes. In this study, we determined the structure of the human Rad50 hook and coiled-coil domains. The data suggest that the predominant structure is the intracomplex, in which the two parallel coiled coils proximal to the hook form a rod shape, and that a novel interface within the coiled-coil domains of Rad50 stabilizes the interaction of Rad50 protomers in the dimeric assembly...
January 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28133604/interaction-of-mre11-and-clinicopathologic-characteristics-in-recurrence-of-breast-cancer-individual-and-cumulated-receiver-operating-characteristic-analyses
#10
Cheng-Hong Yang, Sin-Hua Moi, Li-Yeh Chuang, Shyng-Shiou F Yuan, Ming-Feng Hou, Yi-Chen Lee, Hsueh-Wei Chang
The interaction between the meiotic recombination 11 homolog A (MRE11) oncoprotein and breast cancer recurrence status remains unclear. The aim of this study was to assess the interaction between MRE11 and clinicopathologic variables in breast cancer. A dataset for 254 subjects with breast cancer (220 nonrecurrent and 34 recurrent) was used in individual and cumulated receiver operating characteristic (ROC) analyses of MRE11 and 12 clinicopathologic variables for predicting breast cancer recurrence. In individual ROC analysis, the area under curve (AUC) for each predictor of breast cancer recurrence was smaller than 0...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28132842/dna-double-strand-break-resection-occurs-during-non-homologous-end-joining-in-g1-but-is-distinct-from-resection-during-homologous-recombination
#11
Ronja Biehs, Monika Steinlage, Olivia Barton, Szilvia Juhász, Julia Künzel, Julian Spies, Atsushi Shibata, Penny A Jeggo, Markus Löbrich
Canonical non-homologous end joining (c-NHEJ) repairs DNA double-strand breaks (DSBs) in G1 cells with biphasic kinetics. We show that DSBs repaired with slow kinetics, including those localizing to heterochromatic regions or harboring additional lesions at the DSB site, undergo resection prior to repair by c-NHEJ and not alt-NHEJ. Resection-dependent c-NHEJ represents an inducible process during which Plk3 phosphorylates CtIP, mediating its interaction with Brca1 and promoting the initiation of resection. Mre11 exonuclease, EXD2, and Exo1 execute resection, and Artemis endonuclease functions to complete the process...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28128338/interplay-with-the-mre11-rad50-nbs1-complex-and-phosphorylation-by-gsk3%C3%AE-implicate-human-b-myb-in-dna-damage-signaling
#12
Sarah Marie Henrich, Clemens Usadel, Eugen Werwein, Kamila Burdova, Pavel Janscak, Stefano Ferrari, Daniel Hess, Karl-Heinz Klempnauer
B-Myb, a highly conserved member of the Myb transcription factor family, is expressed ubiquitously in proliferating cells and controls the cell cycle dependent transcription of G2/M-phase genes. Deregulation of B-Myb has been implicated in oncogenesis and loss of genomic stability. We have identified B-Myb as a novel interaction partner of the Mre11-Rad50-Nbs1 (MRN) complex, a key player in the repair of DNA double strand breaks. We show that B-Myb directly interacts with the Nbs1 subunit of the MRN complex and is recruited transiently to DNA-damage sites...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28079255/moonlighting-at-replication-forks-a-new-life-for-homologous-recombination-proteins-brca1-brca2-and-rad51
#13
REVIEW
Arun Mouli Kolinjivadi, Vincenzo Sannino, Anna de Antoni, Hervé Técher, Giorgio Baldi, Vincenzo Costanzo
Coordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked Homologous Recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from Double Strand Break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic ortholog RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA damaging agents...
January 12, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28076794/brca1-directs-the-repair-pathway-to-homologous-recombination-by-promoting-53bp1-dephosphorylation
#14
Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076792/the-mre11-nbs1-interface-is-essential-for-viability-and-tumor-suppression
#15
Jun Hyun Kim, Malgorzata Grosbart, Roopesh Anand, Claire Wyman, Petr Cejka, John H J Petrini
The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1(mid) mice), which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1(mid) alleles that abolished interaction were incompatible with viability...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28073364/lack-of-mre11-rad50-nbs1-mrn-complex-detection-occurs-frequently-in-low-grade-epithelial-ovarian-cancer
#16
Simone Brandt, Eleftherios P Samartzis, Anne-Katrin Zimmermann, Daniel Fink, Holger Moch, Aurelia Noske, Konstantin J Dedes
BACKGROUND: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC)...
January 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28052067/the-paradoxical-effects-of-different-hepatitis-c-viral-loads-on-host-dna-damage-and-repair-abilities
#17
Shu-Chi Wang, Kuan-Ru Lai, Chia-Yang Li, Chi-Shiun Chiang, Guann-Yi Yu, Naoya Sakamoto, Wen-Yu Tu, Meng-Hsuan Hsieh, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai, Ming-Lung Yu
Hepatitis C virus (HCV)-induced hepatic stress is associated with increased oxidative DNA damage and has been implicated in hepatic inflammation. However, HCV infection and replication are uneven and vary among individual hepatocytes. To investigate the effect of the viral load on host DNA damage, we used an Enhanced Yellow Fluorescent Protein gene (EYFP)-tagged HCV virus to distinguish between HCV intracellular high viral load (HVL) cells and low viral load (LVL) cells. The cell sorting efficiency was confirmed by the high expression of the HCV polyprotein...
2017: PloS One
https://www.readbyqxmd.com/read/28031358/association-of-human-papillomavirus-16-e2-with-rad50-interacting-protein-1-enhances-viral-dna-replication
#18
Karen Campos-León, Kalpanee Wijendra, Abida Siddiqa, Ieisha Pentland, Katherine M Feeney, Alison Knapman, Rachel Davies, Elliot J Androphy, Joanna L Parish
Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28002809/preclinical-evaluation-of-the-parp-inhibitor-bmn-673-for-the-treatment-of-ovarian-clear-cell-cancer
#19
Paul M Wilkerson, Konstantin J Dedes, Eleftherios Pierre Samartzis, Ioannis Dedes, Maryou B Lambros, Rachael Natrajan, Arnaud Gauthier, Salvatore Piscuoglio, Chantal Töpfer, Vesna Vukovic, Frances Daley, Britta Weigelt, Jorge S Reis-Filho
PURPOSE: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. EXPERIMENTAL DESIGN: The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27994036/microhomology-mediated-end-joining-is-activated-in-irradiated-human-cells-due-to-phosphorylation-dependent-formation-of-the-xrcc1-repair-complex
#20
Arijit Dutta, Bradley Eckelmann, Sanjay Adhikari, Kazi Mokim Ahmed, Shiladitya Sengupta, Arvind Pandey, Pavana M Hegde, Miaw-Sheue Tsai, John A Tainer, Michael Weinfeld, Muralidhar L Hegde, Sankar Mitra
Microhomology-mediated end joining (MMEJ), an error-prone pathway for DNA double-strand break (DSB) repair, is implicated in genomic rearrangement and oncogenic transformation; however, its contribution to repair of radiation-induced DSBs has not been characterized. We used recircularization of a linearized plasmid with 3'-P-blocked termini, mimicking those at X-ray-induced strand breaks, to recapitulate DSB repair via MMEJ or nonhomologous end-joining (NHEJ). Sequence analysis of the circularized plasmids allowed measurement of relative activity of MMEJ versus NHEJ...
December 19, 2016: Nucleic Acids Research
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