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https://www.readbyqxmd.com/read/27922005/wrn-regulates-pathway-choice-between-classical-and-alternative-non-homologous-end-joining
#1
Raghavendra A Shamanna, Huiming Lu, Jessica K de Freitas, Jane Tian, Deborah L Croteau, Vilhelm A Bohr
Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27918542/the-role-of-break-induced-replication-in-large-scale-expansions-of-cag-n-ctg-n-repeats
#2
Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah, Sergei M Mirkin
Expansions of (CAG)n/(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)n repeats in Saccharomyces cerevisiae...
December 5, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27915381/regulation-of-non-homologous-end-joining-via-post-translational-modifications-of-components-of-the-ligation-step
#3
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/27912094/mre11-is-essential-for-the-removal-of-lethal-topoisomerase-2-covalent-cleavage-complexes
#4
Nguyen Ngoc Hoa, Tsubasa Shimizu, Zhong Wei Zhou, Zhao-Qi Wang, Rajashree A Deshpande, Tanya T Paull, Salma Akter, Masataka Tsuda, Ryohei Furuta, Ken Tsutsui, Shunichi Takeda, Hiroyuki Sasanuma
No abstract text is available yet for this article.
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27889450/rpa-mediates-recruitment-of-mrx-to-forks-and-double-strand-breaks-to-hold-sister-chromatids-together
#5
Andrew Seeber, Anna Maria Hegnauer, Nicole Hustedt, Ishan Deshpande, Jérôme Poli, Jan Eglinger, Philippe Pasero, Heinz Gut, Miki Shinohara, Karl-Peter Hopfner, Kenji Shimada, Susan M Gasser
The Mre11-Rad50-Xrs2 (MRX) complex is related to SMC complexes that form rings capable of holding two distinct DNA strands together. MRX functions at stalled replication forks and double-strand breaks (DSBs). A mutation in the N-terminal OB fold of the 70 kDa subunit of yeast replication protein A, rfa1-t11, abrogates MRX recruitment to both types of DNA damage. The rfa1 mutation is functionally epistatic with loss of any of the MRX subunits for survival of replication fork stress or DSB recovery, although it does not compromise end-resection...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27889449/phosphorylated-ctip-functions-as-a-co-factor-of-the-mre11-rad50-nbs1-endonuclease-in-dna-end-resection
#6
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/27814491/nbs1-converts-the-human-mre11-rad50-nuclease-complex-into-an-endo-exonuclease-machine-specific-for-protein-dna-adducts
#7
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
#8
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/27807099/cyclin-a2-has-a-cdk-independent-role-as-an-rna-binding-protein
#9
(no author information available yet)
Cyclin A2 binds to Mre11 mRNA to promote Mre11 translation and repair of replication errors.
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27798884/high-expression-of-mre11-rad50-nbs1-is-associated-with-poor-prognosis-and-chemoresistance-in-gastric-cancer
#10
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...
October 2016: Anticancer Research
https://www.readbyqxmd.com/read/27783279/frequency-of-pathogenic-germline-mutation-in-chek2-palb2-mre11-and-rad50-in-patients-at-high-risk-for-hereditary-breast-cancer
#11
Haeyoung Kim, Dae-Yeon Cho, Doo Ho Choi, Mijin Oh, Inkyung Shin, Won Park, Seung Jae Huh, Seok Jin Nam, Jeong Eon Lee, Seok Won Kim
PURPOSE: This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer. METHODS: A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing...
October 25, 2016: Breast Cancer Research and Treatment
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
#12
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
#13
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/27746211/insights-into-specificity-redundancy-and-new-cellular-functions-of-c-ebpa-and-c-ebpb-transcription-factors-through-interactome-network-analysis
#14
Maurizio Cirilli, Oxana Bereshchenko, Olga Ermakova, Claus Nerlov
BACKGROUND: C/EBPa and C/EBPb are transcription factors with tissue specific expression regulating several important cellular processes. They work by recruiting protein complexes to a common DNA recognition motif and both are able to compensate each other's absence in many cell types, thus showing functional redundancy. They also play distinct roles in specific cellular pathways and their abnormal functioning gives raise to different human pathologies. METHODS: To investigate the molecular basis of C/EBPa and C/EBPb specificity and redundancy we characterized their in vivo protein-protein interaction networks by Tandem Affinity Purification (TAP) and Mass Spectrometry (MS)...
October 14, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27746018/xrs2-dependent-and-independent-functions-of-the-mre11-rad50-complex
#15
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/27708105/cyclin-a2-is-an-rna-binding-protein-that-controls-mre11-mrna-translation
#16
Arun Kanakkanthara, Karthik B Jeganathan, Jazeel F Limzerwala, Darren J Baker, Masakazu Hamada, Hyun-Ja Nam, Willemijn H van Deursen, Naomi Hamada, Ryan M Naylor, Nicole A Becker, Brian A Davies, Janine H van Ree, Georges Mer, Virginia S Shapiro, L James Maher, David J Katzmann, Jan M van Deursen
Cyclin A2 activates the cyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until early mitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination 11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes...
September 30, 2016: Science
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
#17
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
https://www.readbyqxmd.com/read/27675928/mre11-dysfunction-is-associated-with-triple-negative-breast-cancer-and-confers-sensitivity-to-dna-damaging-therapy
#18
G P Gupta, A Y Ho, W Feng, C Fan, M Akram, E Brogi, S N Powell, C M Perou, Y H Wen, J H J Petrini
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/27673354/pomegranate-intake-protects-against-genomic-instability-induced-by-medical-x-rays-in-vivo-in-mice
#19
Sameera Nallanthighal, Amit B Shirode, Julius A Judd, Ramune Reliene
Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow...
September 27, 2016: Nutrition and Cancer
https://www.readbyqxmd.com/read/27652321/brca1-ctip-interaction-in-the-repair-of-dna-double-strand-breaks
#20
Tomas Aparicio, Jean Gautier
DNA termini at double-strand breaks are often chemically heterogeneous and require processing before initiation of repair. In a recent report, we demonstrated that CtIP and the MRE11-RAD50-NBS1 (MRN) nuclease complex cooperate with BRCA1 to specifically repair topoisomerase II-DNA adducted breaks. In contrast, BRCA1 is dispensable for repair of restriction endonuclease-generated double-strand breaks.
July 2016: Molecular & Cellular Oncology
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