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https://www.readbyqxmd.com/read/29346775/brd4-promotes-dna-repair-and-mediates-the-formation-of-tmprss2-erg-gene-rearrangements-in-prostate-cancer
#1
Xiangyi Li, GuemHee Baek, Susmita G Ramanand, Adam Sharp, Yunpeng Gao, Wei Yuan, Jon Welti, Daniel N Rodrigues, David Dolling, Ines Figueiredo, Semini Sumanasuriya, Mateus Crespo, Adam Aslam, Rui Li, Yi Yin, Bipasha Mukherjee, Mohammed Kanchwala, Ashley M Hughes, Wendy S Halsey, Cheng-Ming Chiang, Chao Xing, Ganesh V Raj, Sandeep Burma, Johann de Bono, Ram S Mani
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29344644/inactivation-of-dna-pk-by-knockdown-dna-pkcs-or-nu7441-impairs-non-homologous-end-joining-of-radiation-induced-double-strand-break-repair
#2
Jun Dong, Yufeng Ren, Tian Zhang, Zhenyu Wang, Clifton C Ling, Gloria C Li, Fuqiu He, Chengtao Wang, Bixiu Wen
The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair...
January 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29333119/phytotherapeutics-oridonin-and-ponicidin-show-additive-effects-combined-with-irradiation-in-pancreatic-cancer-in-vitro
#3
Jakob Liermann, Patrick Naumann, Franco Fortunato, Thomas E Schmid, Klaus-Josef Weber, Jürgen Debus, Stephanie E Combs
Background: Chemoradiation of locally advanced non-metastatic pancreatic cancer can lead to secondary operability by tumor mass reduction. Here, we analyzed radiomodulating effects of oridonin and ponicidin in pancreatic cancer in vitro. Both agents are ent-kaurane diterpenoids, extracted from Isodon rubescens, a plant that is well known in Traditional Chinese Medicine. Cytotoxic effects have recently been shown in different tumor entities for both agents. Materials and methods: Pancreatic cancer cell lines AsPC-1, BxPC-3, Panc-1 and MIA PaCa-2 were pretreated with oridonin or ponicidin and irradiated with 2 Gy to 6 Gy...
December 2017: Radiology and Oncology
https://www.readbyqxmd.com/read/29330493/development-of-versatile-non-homologous-end-joining-based-knock-in-module-for-genome-editing
#4
Shun Sawatsubashi, Yudai Joko, Seiji Fukumoto, Toshio Matsumoto, Shigeo S Sugano
CRISPR/Cas9-based genome editing has dramatically accelerated genome engineering. An important aspect of genome engineering is efficient knock-in technology. For improved knock-in efficiency, the non-homologous end joining (NHEJ) repair pathway has been used over the homology-dependent repair pathway, but there remains a need to reduce the complexity of the preparation of donor vectors. We developed the versatile NHEJ-based knock-in module for genome editing (VIKING). Using the consensus sequence of the time-honored pUC vector to cut donor vectors, any vector with a pUC backbone could be used as the donor vector without customization...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29325827/efficient-oligo-nucleotide-mediated-crispr-cas9-gene-editing-in-aspergilli
#5
Christina S Nødvig, Jakob B Hoof, Martin E Kogle, Zofia D Jarczynska, Jan Lehmbeck, Dorte K Klitgaard, Uffe H Mortensen
CRISPR-Cas9 technologies are revolutionizing fungal gene editing. Here we show that survival of specific Cas9/sgRNA mediated DNA double strand breaks (DSBs) depends on the non-homologous end-joining, NHEJ, DNA repair pathway and we use this observation to develop a tool to assess protospacer efficiency in Aspergillus nidulans. Moreover, we show that in NHEJ deficient strains, highly efficient marker-free gene targeting can be performed. Indeed, we show that even single-stranded oligo nucleotides efficiently works as repair templates of specific Cas9/sgRNA induced DNA DSBs in A...
January 8, 2018: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/29320576/targeting-dna-repair-with-pnkp-inhibition-sensitizes-radioresistant-prostate-cancer-cells-to-high-let-radiation
#6
Pallavi Srivastava, Asitikantha Sarma, Chandra Mohini Chaturvedi
High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator...
2018: PloS One
https://www.readbyqxmd.com/read/29311308/dna-double-strand-break-response-factors-influence-end-joining-features-of-igh-class-switch-and-general-translocation-junctions
#7
Rohit A Panchakshari, Xuefei Zhang, Vipul Kumar, Zhou Du, Pei-Chi Wei, Jennifer Kao, Junchao Dong, Frederick W Alt
Ig heavy chain (IgH) class switch recombination (CSR) in B lymphocytes switches IgH constant regions to change antibody functions. CSR is initiated by DNA double-strand breaks (DSBs) within a donor IgH switch (S) region and a downstream acceptor S region. CSR is completed by fusing donor and acceptor S region DSB ends by classical nonhomologous end-joining (C-NHEJ) and, in its absence, by alternative end-joining that is more biased to use longer junctional microhomologies (MHs). Deficiency for DSB response (DSBR) factors, including ataxia telangiectasia-mutated (ATM) and 53BP1, variably impair CSR end-joining, with 53BP1 deficiency having the greatest impact...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29298990/gsk3%C3%AE-negatively-regulates-trax-a-scaffold-protein-implicated-in-mental-disorders-for-nhej-mediated-dna-repair-in-neurons
#8
Ting Chien, Yu-Ting Weng, Shu-Yung Chang, Hsing-Lin Lai, Feng-Lan Chiu, Hung-Chih Kuo, De-Maw Chuang, Yijuang Chern
Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gsα protein-coupled receptor, the A2A adenosine receptor (A2AR), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A2AR markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3β) and disrupted-in-schizophrenia 1 (DISC1) are two novel interacting proteins of TRAX...
January 3, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29247009/nonhomologous-dna-end-joining-for-repair-of-dna-double-strand-breaks
#9
Nicholas R Pannunzio, Go Watanabe, Michael R Lieber
Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases.  NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol μ and Pol λ), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex).  Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB...
December 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29238067/alternative-nhej-pathway-proteins-as-components-of-mycn-oncogenic-activity-in-human-neural-crest-stem-cell-differentiation-implications-for-neuroblastoma-initiation
#10
Erika A Newman, Sahiti Chukkapalli, Daniela Bashllari, Tina T Thomas, Raelene A Van Noord, Elizabeth R Lawlor, Mark J Hoenerhoff, Anthony W Opipari, Valerie P Opipari
Neuroblastoma is a cancer of neural crest stem cell (NCSC) lineage. Signaling pathways that regulate NCSC differentiation have been implicated in neuroblastoma tumorigenesis. This is exemplified by MYCN oncogene targets that balance proliferation, differentiation, and cell death similarly in normal NCSC and in high-risk neuroblastoma. Our previous work discovered a survival mechanism by which MYCN-amplified neuroblastoma circumvents cell death by upregulating components of the error-prone non-canonical alternative nonhomologous end-joining (alt-NHEJ) DNA repair pathway...
December 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29237014/the-effect-of-stochasticity-on-repair-of-dna-double-strand-breaks-throughout-non-homologous-end-joining-pathway
#11
Fazeleh S Mohseni-Salehi, Fatemeh Zare-Mirakabad, Soudeh Ghafouri-Fard, Mehdi Sadeghi
DNA double strand breaks (DSBs) are the most lethal lesions of DNA induced by ionizing radiation, industrial chemicals and a wide variety of drugs used in chemotherapy. In the context of DNA damage response system modelling, uncertainty may arise in several ways such as number of induced DSBs, kinetic rates and measurement error in observable quantities. Therefore, using the stochastic approaches is imperative to gain further insight into the dynamic behaviour of DSBs repair process. In this article, a continuous-time Markov chain (CTMC) model of the non-homologous end joining (NHEJ) mechanism is formulated according to the DSB complexity...
December 8, 2017: Mathematical Medicine and Biology: a Journal of the IMA
https://www.readbyqxmd.com/read/29234047/inhibition-of-nhej-repair-by-type-ii-a-crispr-cas-systems-in-bacteria
#12
Aude Bernheim, Alicia Calvo-Villamañán, Clovis Basier, Lun Cui, Eduardo P C Rocha, Marie Touchon, David Bikard
Type II CRISPR-Cas systems introduce double-strand breaks into DNA of invading genetic material and use DNA fragments to acquire novel spacers during adaptation. These breaks can be the substrate of several DNA repair pathways, paving the way for interactions. We report that non-homologous end-joining (NHEJ) and type II-A CRISPR-Cas systems only co-occur once among 5563 fully sequenced prokaryotic genomes. We investigated experimentally the possible molecular interactions using the NHEJ pathway from Bacillus subtilis and the type II-A CRISPR-Cas systems from Streptococcus thermophilus and Streptococcus pyogenes...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29234018/dynamics-of-rif1-sumoylation-is-regulated-by-pias4-in-the-maintenance-of-genomic-stability
#13
Ramesh Kumar, Cheok Chit Fang
RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29232168/high-throughput-screening-approach-for-identifying-compounds-that-inhibit-nonhomologous-end-joining
#14
Andrea L Bredemeyer, Bruce S Edwards, Mark K Haynes, Abigail J Morales, Yinan Wang, Oleg Ursu, Anna Waller, Larry A Sklar, Barry P Sleckman
DNA double-strand breaks (DSBs) are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ). Compounds that modulate HR have shown promise as cancer therapeutics. The V(D)J recombination reaction, which assembles antigen receptor genes in lymphocytes, is initiated by the introduction of DNA DSBs at two recombining gene segments by the RAG endonuclease, followed by the NHEJ-mediated repair of these DSBs. Here, using HyperCyt automated flow cytometry, we develop a robust high-throughput screening (HTS) assay for NHEJ that utilizes engineered pre-B-cell lines where the V(D)J recombination reaction can be induced and monitored at a single-cell level...
December 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#15
Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29228718/increased-single-strand-annealing-rather-than-non-homologous-end-joining-predicts-hereditary-ovarian-carcinoma
#16
Miriam Deniz, Tatiana Romashova, Sarah Kostezka, Anke Faul, Theresa Gundelach, Maria Moreno-Villanueva, Wolfgang Janni, Thomas W P Friedl, Lisa Wiesmüller
Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29227966/pot1-inhibits-the-efficiency-but-promotes-the-fidelity-of-nonhomologous-end-joining-at-non-telomeric-dna-regions
#17
Yang Yu, Rong Tan, Qian Ren, Boya Gao, Zhejin Sheng, Juanlian Zhang, Xiaoqing Zheng, Ying Jiang, Li Lan, Zhiyong Mao
Robust DNA double strand break (DSB) repair and stabilized telomeres help maintain genome integrity, preventing the onset of aging or tumorigenesis. POT1 is one of the six factors in the shelterin complex, which protects telomeres from being recognized as DNA damages. TRF1 and TRF2, two other shelterin proteins, have been shown to participate in DNA DSB repair at non-telomeric regions, but whether POT1, which binds to single strand telomeric DNA at chromosomal ends, is involved in DNA DSB repair has not been assessed...
December 8, 2017: Aging
https://www.readbyqxmd.com/read/29227281/targeting-mcl-1-enhances-dna-replication-stress-sensitivity-to-cancer-therapy
#18
Guo Chen, Andrew T Magis, Ke Xu, Dongkyoo Park, David S Yu, Taofeek K Owonikoko, Gabriel L Sica, Sarah W Satola, Suresh S Ramalingam, Walter J Curran, Paul W Doetsch, Xingming Deng
DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29223136/allele-exchange-at-the-epsps-locus-confers-glyphosate-tolerance-in-cassava
#19
Aaron W Hummel, Raj Deepika Chauhan, Tomas Cermak, Andrew M Mutka, Anupama Vijayaraghavan, Adam Boyher, Colby G Starker, Rebecca Bart, Daniel F Voytas, Nigel J Taylor
Effective weed control can protect yields of cassava (Manihot esculenta) storage roots (Doll and Piedrahita Cañola, 1978). Farmers could benefit from using herbicide with a tolerant cultivar. We applied traditional transgenesis and gene editing to generate robust glyphosate tolerance in cassava. By comparing promoters regulating expression of transformed 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) genes with various paired amino acid substitutions, we found that strong constitutive expression is required to achieve glyphosate tolerance during in vitro selection and in whole cassava plants...
December 9, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29222170/imprecision-and-dna-break-repair-biased-towards-incompatible-end-joining-in-leukemia
#20
Franz Josef Gassner, Maria Schubert, Stefan Rebhandl, Karina Spandl, Nadja Zaborsky, Kemal Catakovic, Stephanie Blaimer, Daniel Hebenstreit, Richard Greil, Roland Geisberger
Cancer is a genetic disease caused by mutations and chromosomal abnormalities which contribute to uncontrolled cell growth. In addition, cancer cells can rapidly respond to conventional and targeted therapies by accumulating novel and often specific genetic lesions leading to acquired drug resistance and relapsing disease. In chronic lymphocytic leukemia (CLL), however, diverse chromosomal aberrations often occur. In many cases, improper repair of DNA double strand breaks (DSBs) is a major source for genomic abnormalities...
December 8, 2017: Molecular Cancer Research: MCR
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