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https://www.readbyqxmd.com/read/28178691/p-glycoprotein-attenuates-dna-repair-activity-in-multidrug-resistant-cells-by-acting-through-the-cbp-csk-src-cascade
#1
Li-Fang Lin, Ming-Hsi Wu, Vijaya Kumar Pidugu, I-Ching Ho, Tsann-Long Su, Te-Chang Lee
Recent studies have demonstrated that P-glycoprotein (P-gp) expression impairs DNA interstrand cross-linking agent-induced DNA repair efficiency in multidrug-resistant (MDR) cells. To date, the detailed molecular mechanisms underlying how P-gp interferes with Src activation and subsequent DNA repair activity remain unclear. In this study, we determined that the C-terminal Src kinase-binding protein (Cbp) signaling pathway involved in the negative control of Src activation is enhanced in MDR cells. We also demonstrated that cells that ectopically express P-gp exhibit reduced activation of DNA damage response regulators, such as ATM, Chk2, Braca1 and Nbs1 and hence attenuated DNA double-strand break repair capacity and become more susceptible than vector control cells to DNA interstrand cross-linking (ICL) agents...
February 3, 2017: Oncotarget
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
#2
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/28128338/interplay-with-the-mre11-rad50-nbs1-complex-and-phosphorylation-by-gsk3%C3%AE-implicate-human-b-myb-in-dna-damage-signaling
#3
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/28107384/an-approach-to-elucidate-nbs1-function-in-dna-repair-using-frequent-nonsynonymous-polymorphism-in-wild-medaka-oryzias-latipes-populations
#4
Kento Igarashi, Junya Kobayashi, Takafumi Katsumura, Yusuke Urushihara, Kyohei Hida, Tomomi Watanabe-Asaka, Hiroki Oota, Shoji Oda, Hiroshi Mitani
Nbs1 is one of the genes responsible for Nijmegen breakage syndrome, which is marked with high radiosensitivity. In human NBS1 (hNBS1), Q185E polymorphism is known as the factor to cancer risks, although its DSB repair defect has not been addressed. Here we investigated the genetic variations in medaka (Oryzias latipes) wild populations, and found 40 nonsynonymous single nucleotide polymorphisms (SNPs) in medaka nbs1 (olnbs1) gene within 5 inbred strains. A mutation to histidine in Q170 residue in olNbs1, which corresponds to Q185 residue of hNBS1, was widely distributed in the closed colonies derived from the eastern Korean population of medaka...
2017: PloS One
https://www.readbyqxmd.com/read/28076792/the-mre11-nbs1-interface-is-essential-for-viability-and-tumor-suppression
#5
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
#6
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/28031358/association-of-human-papillomavirus-type-16-e2-with-rad50-interacting-protein-1-enhances-viral-dna-replication
#7
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 S phase to G2/M transition and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi to the endoplasmic reticulum (ER) through interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus type 16 (HPV16) transcription and replication factor E2...
December 28, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27932484/role-of-mdm2-and-mdmx-in-dna-repair
#8
REVIEW
Christine M Eischen
Mdm2 and Mdmx are critical regulators of the p53 tumour suppressor and are overexpressed in many human malignancies. However, in recent years, their impact on genome instability was shown to be at least, in part, independent of p53. Both Mdm2 and Mdmx inhibit DNA break repair through their association with the Mre11/Rad50/Nbs1 DNA repair complex. Recent evidence indicates that harnessing Mdm2 and/or Mdmx-mediated inhibition of DNA break repair in cancer cells could provide a therapeutic opportunity, particularly for those malignancies that have lost functional p53...
December 8, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27918544/a-balance-between-elongation-and-trimming-regulates-telomere-stability-in-stem-cells
#9
Teresa Rivera, Candy Haggblom, Sandro Cosconati, Jan Karlseder
Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively...
January 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27889449/phosphorylated-ctip-functions-as-a-co-factor-of-the-mre11-rad50-nbs1-endonuclease-in-dna-end-resection
#10
Roopesh Anand, Lepakshi Ranjha, Elda Cannavo, Petr Cejka
To repair a DNA double-strand break (DSB) by homologous recombination (HR), the 5'-terminated strand of the DSB must be resected. The human MRE11-RAD50-NBS1 (MRN) and CtIP proteins were implicated in the initiation of DNA end resection, but the underlying mechanism remained undefined. Here, we show that CtIP is a co-factor of the MRE11 endonuclease activity within the MRN complex. This function is absolutely dependent on CtIP phosphorylation that includes the key cyclin-dependent kinase target motif at Thr-847...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27845421/rs2735383-located-at-a-microrna-binding-site-in-the-3-utr-of-nbs1-is-not-associated-with-breast-cancer-risk
#11
Jingjing Liu, Ivona Lončar, J Margriet Collée, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, Irene L Andrulis, Monica Barile, Matthias W Beckmann, Sabine Behrens, Javier Benitez, Carl Blomqvist, Bram Boeckx, Natalia V Bogdanova, Stig E Bojesen, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Jenny Chang-Claude, Shou-Tung Chen, Georgia Chenevix-Trench, Ching Y Cheng, Ji-Yeob Choi, Fergus J Couch, Angela Cox, Simon S Cross, Katarina Cuk, Kamila Czene, Thilo Dörk, Isabel Dos-Santos-Silva, Peter A Fasching, Jonine Figueroa, Henrik Flyger, Montserrat García-Closas, Graham G Giles, Gord Glendon, Mark S Goldberg, Anna González-Neira, Pascal Guénel, Christopher A Haiman, Ute Hamann, Steven N Hart, Mikael Hartman, Sigrid Hatse, John L Hopper, Hidemi Ito, Anna Jakubowska, Maria Kabisch, Daehee Kang, Veli-Matti Kosma, Vessela N Kristensen, Loic Le Marchand, Eunjung Lee, Jingmei Li, Artitaya Lophatananon, Jan Lubinski, Arto Mannermaa, Keitaro Matsuo, Roger L Milne, Susan L Neuhausen, Heli Nevanlinna, Nick Orr, Jose I A Perez, Julian Peto, Thomas C Putti, Katri Pylkäs, Paolo Radice, Suleeporn Sangrajrang, Elinor J Sawyer, Marjanka K Schmidt, Andreas Schneeweiss, Chen-Yang Shen, Martha J Shrubsole, Xiao-Ou Shu, Jacques Simard, Melissa C Southey, Anthony Swerdlow, Soo H Teo, Daniel C Tessier, Somchai Thanasitthichai, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Celine Vachon, Robert Winqvist, Anna H Wu, Drakoulis Yannoukakos, Wei Zheng, Per Hall, Alison M Dunning, Douglas F Easton, Maartje J Hooning, Ans M W van den Ouweland, John W M Martens, Antoinette Hollestelle
NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27814491/nbs1-converts-the-human-mre11-rad50-nuclease-complex-into-an-endo-exonuclease-machine-specific-for-protein-dna-adducts
#12
Rajashree A Deshpande, Ji-Hoon Lee, Sucheta Arora, Tanya T Paull
The human Mre11/Rad50/Nbs1 (hMRN) complex is critical for the sensing, processing, and signaling of DNA double-strand breaks. The nuclease activity of Mre11 is essential for mammalian development and cell viability, although the regulation and substrate specificity of Mre11 have been difficult to define. Here we show that hMRN catalyzes sequential endonucleolytic and exonucleolytic activities on both 5' and 3' strands of DNA ends containing protein adducts, and that Nbs1, ATP, and adducts are essential for this function...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27814490/mre11-is-essential-for-the-removal-of-lethal-topoisomerase-2-covalent-cleavage-complexes
#13
Nguyen Ngoc Hoa, Tsubasa Shimizu, Zhong Wei Zhou, Zhao-Qi Wang, Rajashree A Deshpande, Tanya T Paull, Salma Akter, Masataka Tsuda, Ryohei Furuta, Ken Tsusui, Shunichi Takeda, Hiroyuki Sasanuma
The Mre11/Rad50/Nbs1 complex initiates double-strand break repair by homologous recombination (HR). Loss of Mre11 or its nuclease activity in mouse cells is known to cause genome aberrations and cellular senescence, although the molecular basis for this phenotype is not clear. To identify the origin of these defects, we characterized Mre11-deficient (MRE11(-/-)) and nuclease-deficient Mre11 (MRE11(-/H129N)) chicken DT40 and human lymphoblast cell lines. These cells exhibit increased spontaneous chromosomal DSBs and extreme sensitivity to topoisomerase 2 poisons...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27798884/high-expression-of-mre11-rad50-nbs1-is-associated-with-poor-prognosis-and-chemoresistance-in-gastric-cancer
#14
Bolag Altan, Takehiko Yokobori, Munenori Ide, Tuya Bai, Toru Yanoma, Akiharu Kimura, Norimichi Kogure, Masaki Suzuki, Pinjie Bao, Erito Mochiki, Kyoichi Ogata, Tadashi Handa, Kyoichi Kaira, Masahiko Nishiyama, Takayuki Asao, Tetsunari Oyama, Hiroyuki Kuwano
BACKGROUND: The MRN complex of meiotic recombination 11 (MRE11), DNA repair protein Rad50 (RAD50) and Nijmegen breakage syndrome 1 (NBS1) proteins coordinate the detection and repair of DNA double-strand breaks (DSBs). DNA DSB repair-dependent chemoresistance likely has an effect on the treatment of human cancer. MATERIALS AND METHODS: We investigated the expression of MRN complex in human gastric cancer (GC) tissues using immunohistochemistry and analyzed its clinical significance and prognostic relevance...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27785413/t-lymphoblastic-leukemia-lymphoma-in-macedonian-patients-with-nijmegen-breakage-syndrome
#15
S A Kocheva, K Martinova, Z Antevska-Trajkova, B Coneska-Jovanova, A Eftimov, A J Dimovski
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to malignancy. The gene responsible for the disease, NBS1, is located on chromosome 8q21 and encodes a protein called nibrin. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS. In this report, we describe two patients with NBS and T-lymphoblastic leukemia/lymphoma in a Macedonian family...
July 1, 2016: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/27770701/the-rb-binding-domain-of-hpv31-e7-is-required-to-maintain-high-levels-of-dna-repair-factors-in-infected-cells
#16
Bryan A Johnson, Heather L Aloor, Cary A Moody
Human papillomaviruses (HPV) exhibit constitutive activation of ATM and ATR DNA damage response (DDR) pathways, which are required for productive viral replication. Expression of HPV31 E7 alone is sufficient to activate the DDR through an unknown mechanism. Here, we demonstrate that the E7 Rb binding domain is required to increase levels of many DDR proteins, including ATM, Chk2, Chk1, the MRN components MRE11, Rad50, and NBS1, as well as the homologous recombination repair proteins BRCA1 and Rad51. Interestingly, we have found that the increase in these DNA repair proteins does not occur solely at the level of transcription, but that E7 broadly increases the half-life of these DDR factors, a phenotype that is lost in the E7 Rb binding mutant...
October 19, 2016: Virology
https://www.readbyqxmd.com/read/27765104/-mutant-rad50-enhances-killing-effects-of-radiation-on-nasopharyngeal-carcinoma-cell-line-cne1
#17
R C Yan, J Wang, Z Z Huang, Z Y Wang, X F Wu, J C Huang, L H Chang, D Q Li, G H Zhang
Objective: To investigate the killing effects of radiation and mutant Rad50 transfection on human nasopharyngeal carcinoma cell line CNE1. Methods: The experimental groups included: control group, Ad-Rad50-GFP group, Ad-EGFP group, irradiation group, Ad-Rad50-GFP combined with irradiation group, and Ad-EGFP combined with irradiation group. CNE1 cells were transfected with recombinant adenoviral vector Ad-Rad50-GFP carrying mutant Rad50 gene. The expressions of Mre11, Rad50, Nbs1, and relevant constituents composing MRN complex were detected by Western Blot...
October 7, 2016: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke za Zhi, Chinese Journal of Otorhinolaryngology Head and Neck Surgery
https://www.readbyqxmd.com/read/27746018/xrs2-dependent-and-independent-functions-of-the-mre11-rad50-complex
#18
Julyun Oh, Amr Al-Zain, Elda Cannavo, Petr Cejka, Lorraine S Symington
The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex orchestrates the cellular response to DSBs through its structural, enzymatic, and signaling roles. Xrs2/Nbs1 is essential for nuclear translocation of Mre11, but its role as a component of the complex is not well defined. Here, we demonstrate that nuclear localization of Mre11 (Mre11-NLS) is able to bypass several functions of Xrs2, including DNA end resection, meiosis, hairpin resolution, and cellular resistance to clastogens. Using purified components, we show that the MR complex has equivalent activity to MRX in cleavage of protein-blocked DNA ends...
October 20, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27726944/effect-of-silencing-key-proteins-in-telomerase-mechanism-and-alternative-lengthening-of-telomeres-mechanism-in-laryngeal-cancer-cells
#19
Yong Xu, Xiao Wang, Shi-Ming Chen, Chen Chen, Yan Wang, Bo-Kui Xiao, Ze-Zhang Tao
PURPOSE: To explore the influences of telomerase and alternative lengthening of telomeres mechanism on telomere length and laryngeal squamous cell carcinoma in vitro and in vivo. MATERIALS AND METHODS: Short hairpin RNA expression vectors targeting the messenger TERT, TRF2, RAD51 and NBS1 were constructed. The mRNA and protein expression of targeted genes in human laryngeal squamous carcinoma cell line HEp-2 was evaluated by reverse transcription polymerase chain reaction and Western blotting separately...
November 2016: American Journal of Otolaryngology
https://www.readbyqxmd.com/read/27684057/proteomic-profiling-reveals-the-induction-of-upr-in-addition-to-dna-damage-response-in-hela-cells-treated-with-the-thiazolo-5-4-b-quinoline-derivative-d3clp
#20
José Carlos Páez-Franco, Ignacio González-Sánchez, Nora A Gutiérrez-Nájera, Lilián G Valencia-Turcotte, Alfonso Lira-Rocha, Marco A Cerbón, Rogelio Rodríguez-Sotres
9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinolone (D3ClP) is a bioisostere of N-(4-(acridin-9-ylamino)-3-methoxyphenyl)methanesulfonamide (m-AMSA) a DNA topoisomerase II inhibitor with proven cytotoxic activity and known to induce DNA damage and apoptotic cell death in K562 cells. However, recent evidence is not consistent with DNA topoisomerase II (DNA TOP2) as the primary target of D3ClP, in contrast to m-AMSA. We provide evidence of histone γH2AX phosphorylation at Ser135 in HeLa cells treated with D3ClP, a marker of DNA double strand repair through Mre11-Rad50-Nbs1 (MRN) pathway...
September 29, 2016: Journal of Cellular Biochemistry
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