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https://www.readbyqxmd.com/read/29655920/suppressing-ku70-ku80-expression-elevates-homology-directed-repair-efficiency-in-primary-fibroblasts
#1
Guoling Li, Dewu Liu, Xianwei Zhang, Rong Quan, Cuili Zhong, Jianxin Mo, Yaoqiang Huang, Haoqiang Wang, Xiaofang Ruan, Zheng Xu, Enqin Zheng, Ting Gu, Linjun Hong, Zicong Li, Zhenfang Wu, Huaqiang Yang
The main DNA repair pathways, nonhomologous end joining (NHEJ) and homology-directed repair (HDR), are complementary to each other; hence, interruptions of the NHEJ pathway can favor HDR. Improving HDR efficiency in animal primary fibroblasts can facilitate the generation of gene knock-in animals with agricultural and biomedical values by somatic cell nuclear transfer. In this study, we used siRNA to suppress the expression of Ku70 and Ku80, which are the key factors in NHEJ pathway, to investigate the effect of Ku silencing on the HDR efficiency in pig fetal fibroblasts...
April 12, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29566071/improving-the-efficiency-of-homologous-recombination-by-chemical-and-biological-approaches-in-yarrowia-lipolytica
#2
In-Seung Jang, Byung Jo Yu, Ji Yeon Jang, Jonggeon Jegal, Ju Young Lee
Gene targeting is a challenge in Yarrowia lipolytica (Y. lipolytica) where non-homologous end-joining (NHEJ) is predominant over homologous recombination (HR). To improve the frequency and efficiency of HR in Y. lipolytica, the ku70 gene responsible for a double stand break (DSB) repair in the NHEJ pathway was disrupted, and the cell cycle was synchronized to the S-phase with hydroxyurea, respectively. Consequently, the HR frequency was over 46% with very short homology regions (50 bp): the pex10 gene was accurately deleted at a frequency of 60% and the β-carotene biosynthetic genes were integrated at the correct locus at an average frequency of 53%...
2018: PloS One
https://www.readbyqxmd.com/read/29564828/genes-proteins-and-biological-pathways-preventing-chromothripsis
#3
Martin Poot
The highly complex structural genome variations chromothripsis, chromoanasynthesis, and chromoplexy are subsumed under the term chromoanagenesis, which means chromosome rebirth. Precipitated by numerous DNA double-strand breaks, they differ in number of and distances between breakpoints, associated copy number variations, order and orientation of segments, and flanking sequences at joining points. Results from patients with the autosomal dominant cancer susceptibility disorder Li-Fraumeni syndrome implicated somatic TP53 mutations in chromothripsis...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29557773/a-highly-efficient-genetic-system-for-the-identification-of-a-harzianum-b-biosynthetic-gene-cluster-in-trichoderma-hypoxylon
#4
Huan Liu, Gang Wang, Wei Li, Xingzhong Liu, Erwei Li, Wen-Bing Yin
Trichoderma hypoxylon is a fungicolous species which produces rich secondary metabolites. However, no genetic transformation method is available for further studies. Here, we developed a marker-less transformation system based on the complementation of an uridine/uracil biosynthetic gene by protoplast transformation. An uridine/uracil auxotrophic mutant of Δthpyr4 was obtained by using a positive screening protocol with 5'-fluoroorotic acid as a selective reagent. To improve the homologous integration rates, the orthologues of ku70 and lig4 which play critical roles in non-homologous end-joining recombination were disrupted...
March 19, 2018: Microbiology
https://www.readbyqxmd.com/read/29556331/niclosamide-sensitizes-nasopharyngeal-carcinoma-to-radiation-by-downregulating-ku70-80-expression
#5
Jingjing Li, Haiwen Li, Dechao Zhan, Mei Xiang, Jun Yang, Yufang Zuo, Yin Yu, Hechao Zhou, Danxian Jiang, Haiqing Luo, Zihong Chen, Zhonghua Yu, Zumin Xu
The aim of the present study was to investigate whether niclosamide could sensitize the nasopharyngeal carcinoma cells to radiation and further explore the underlying mechanisms. CCK-8 assay was used to determine the effect of niclosamide on the proliferation of NPC cells. Colony formation assay was used to evaluate the radiosensitizing effect of niclosamide on NPC cells. Flow cytometry analysis was used to determine the apoptosis of NPC cells induced by niclosamide. Immunofluorescent staining was used to detect the formation of γ-H2AX foci and the localization of Ku70/80 proteins in NPC cells...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29523244/recovery-of-alternative-end-joining-repair-products-from-drosophila-embryos
#6
Terrence Hanscom, Varandt Y Khodaverdian, Mitch McVey
In this chapter, we describe a method for the recovery and analysis of alternative end-joining (alt-EJ) DNA double-strand break repair junctions following I-SceI cutting in Drosophila melanogaster embryos. Alt-EJ can be defined as a set of Ku70/80 and DNA ligase 4-independent end-joining processes that are typically mutagenic, producing deletions, insertions, and chromosomal rearrangements more frequently than higher-fidelity repair pathways such as classical nonhomologous end joining or homologous recombination...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29522548/yeast-based-assays-for-characterization-of-the-functional-effects-of-single-nucleotide-polymorphisms-in-human-dna-repair-genes
#7
Changshin Kim, Jinmo Yang, Su-Hyun Jeong, Hayoung Kim, Geun-Hee Park, Hwa Beom Shin, MyungJa Ro, Kyoung-Yeon Kim, YoungJoon Park, Keun Pil Kim, KyuBum Kwack
DNA repair mechanisms maintain genomic integrity upon exposure to various types of DNA damage, which cause either single- or double-strand breaks in the DNA. Here, we propose a strategy for the functional study of single nucleotide polymorphisms (SNPs) in the human DNA repair genes XPD/ERCC2, RAD18, and KU70/XRCC6 and the checkpoint activation gene ATR that are essentially involved in the cell cycle and DNA damage repair. We analyzed the mutational effects of the DNA repair genes under DNA-damaging conditions, including ultraviolet irradiation and treatment with genotoxic reagents, using a Saccharomyces cerevisiae system to overcome the limitations of the human cell-based assay...
2018: PloS One
https://www.readbyqxmd.com/read/29511621/robust-dna-repair-in-paxx-deficient-mammalian-cells
#8
Alisa Dewan, Mengtan Xing, Marie Benner Lundbæk, Raquel Gago-Fuentes, Carole Beck, Per Arne Aas, Nina-Beate Liabakk, Siri Sæterstad, Khac Thanh Phong Chau, Bodil Merete Kavli, Valentyn Oksenych
To ensure genome stability, mammalian cells employ several DNA repair pathways. Nonhomologous DNA end joining (NHEJ) is the DNA repair process that fixes double-strand breaks throughout the cell cycle. NHEJ is involved in the development of B and T lymphocytes through its function in V(D)J recombination and class switch recombination (CSR). NHEJ consists of several core and accessory factors, including Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, Artemis, and XLF. Paralog of XRCC4 and XLF (PAXX) is the recently described accessory NHEJ factor that structurally resembles XRCC4 and XLF and interacts with Ku70/Ku80...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29511619/normal-development-of-mice-lacking-paxx-the-paralogue-of-xrcc4-and-xlf
#9
Raquel Gago-Fuentes, Mengtan Xing, Siri Sæterstad, Antonio Sarno, Alisa Dewan, Carole Beck, Stefano Bradamante, Magnar Bjørås, Valentyn Oksenych
DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29453554/in-vitro-studies-of-dna-damage-and-repair-mechanisms-induced-by-bnct-in-a-poorly-differentiated-thyroid-carcinoma-cell-line
#10
C Rodriguez, M Carpano, P Curotto, S Thorp, M Casal, G Juvenal, M Pisarev, M A Dagrosa
Boron neutron capture therapy (BNCT) for aggressive tumors is based on nuclear reaction [ 10 B (n, α) 7 Li]. Previously, we demonstrated that BNCT could be applied for the treatment of undifferentiated thyroid carcinoma. The aim of the present study was to describe the DNA damage pattern and the repair pathways that are activated by BNCT in thyroid cells. We analyzed γH2AX foci and the expression of Ku70, Rad51 and Rad54, main effector enzymes of non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways, respectively, in thyroid follicular carcinoma cells...
February 16, 2018: Radiation and Environmental Biophysics
https://www.readbyqxmd.com/read/29447383/super-resolution-imaging-identifies-parp1-and-the-ku-complex-acting-as-dna-double-strand-break-sensors
#11
Guang Yang, Chao Liu, Shih-Hsun Chen, Muzaffer A Kassab, J Damon Hoff, Nils G Walter, Xiaochun Yu
DNA double-strand breaks (DSBs) are fatal DNA lesions and activate a rapid DNA damage response. However, the earliest stage of DSB sensing remains elusive. Here, we report that PARP1 and the Ku70/80 complex localize to DNA lesions considerably earlier than other DSB sensors. Using super-resolved fluorescent particle tracking, we further examine the relocation kinetics of PARP1 and the Ku70/80 complex to a single DSB, and find that PARP1 and the Ku70/80 complex are recruited to the DSB almost at the same time...
February 13, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29423093/combination-of-a-hypomethylating-agent-and-inhibitors-of-parp-and-hdac-traps-parp1-and-dnmt1-to-chromatin-acetylates-dna-repair-proteins-down-regulates-nurd-and-induces-apoptosis-in-human-leukemia-and-lymphoma-cells
#12
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29415883/temporal-dna-pk-activation-drives-genomic-instability-and-therapy-resistance-in-glioma-stem-cells
#13
Yanling Wang, Haineng Xu, Tianrun Liu, Menggui Huang, Param-Puneet Butter, Chunsheng Li, Lin Zhang, Gary D Kao, Yanqing Gong, Amit Maity, Constantinos Koumenis, Yi Fan
Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA-PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance...
February 8, 2018: JCI Insight
https://www.readbyqxmd.com/read/29397516/role-of-polymorphic-xrcc6-ku70-xrcc7-dna-pkcs-genes-towards-susceptibility-and-prognosis-of-lung-cancer-patients-undergoing-platinum-based-doublet-chemotherapy
#14
Amrita Singh, Navneet Singh, Digambar Behera, Siddharth Sharma
The DNA repair genes XRCC6 and XRCC7 formed an integral part of double strand break repair (DSBR) pathway. The two genes are thought to play an important role in the repair of lethal double strand damage on DNA. Polymorphic DSBR genes are studied to effect genomic stability. We intend to explore the association of DSBR genes i.e. XRCC6 and XRCC7 with susceptibility and survival in North Indian lung cancer patients. DNA isolation and genotyping was done for 320 controls and 330 lung cancer cases enrolled in the study...
February 3, 2018: Molecular Biology Reports
https://www.readbyqxmd.com/read/29393484/effect-of-sinomenine-hydrochloride-on-radiosensitivity-of-esophageal-squamous-cell-carcinoma-cells
#15
Shenbo Fu, Long Jin, Tuotuo Gong, Shupei Pan, Shuyu Zheng, Xuanwei Zhang, Tian Yang, Yuchen Sun, Ya Wang, Jia Guo, Beina Hui, Xiaozhi Zhang
Radiation therapy is one of the most important treatments for unresectable and locally advanced esophageal squamous cell carcinoma (ESCC), however, the response to radiotherapy is sometimes limited by the development of radioresistance. Sinomenine hydrochloride (SH) has anticancer activity, but its effect on the radiosensitivity of ESCC is unclear. We determined the effect of SH on the radiosensitivity of ESCC cells and elucidated its potential radiosensitization mechanisms in vitro and in vivo. ESCC cells were subjected to SH and radiation, both separately and in combination...
April 2018: Oncology Reports
https://www.readbyqxmd.com/read/29333119/phytotherapeutics-oridonin-and-ponicidin-show-additive-effects-combined-with-irradiation-in-pancreatic-cancer-in-vitro
#16
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/29328366/expression-of-dna-damage-response-proteins-in-gastric-cancer-comprehensive-protein-profiling-and-histological-analysis
#17
Hiroki Arai, Ryuichi Wada, Kousuke Ishino, Mitsuhiro Kudo, Eiji Uchida, Zenya Naito
Gastric cancer is the third major cause of cancer-related mortality in Japan. The aim of this study was to identify a factor implicated in the biology of gastric cancer by comprehensive protein profiling. Protein profiling was carried out by liquid chromatography-tandem mass spectrometry, using formalin-fixed paraffin-embedded specimens of 17 gastric cancer cases. Pathway analysis and orthogonal partial least square-discriminant analysis suggested the significant expression of ribonucleoproteins, heterogeneous nuclear ribonucleoproteins, interleukin binding factor 2 (ILF2), KU70 and KU80, which are involved in DNA damage response (DDR)...
March 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29278895/aberrant-caspase-activation-in-laminin-%C3%AE-2-deficient-human-myogenic-cells-is-mediated-by-p53-and-sirtuin-activity
#18
Soonsang Yoon, Mary Lou Beermann, Bryant Yu, Di Shao, Markus Bachschmid, Jeffrey Boone Miller
BACKGROUND: Mutations in the LAMA2 gene encoding laminin-α2 cause congenital muscular dystrophy Type 1A (MDC1A), a severe recessive disease with no effective treatment. Previous studies have shown that aberrant activation of caspases and cell death through a pathway regulated by BAX and KU70 is a significant contributor to pathogenesis in laminin-α2-deficiency. OBJECTIVES: To identify mechanisms of pathogenesis in MDC1A. METHODS: We used immunocytochemical and molecular studies of human myogenic cells and mouse muscles-comparing laminin-α2-deficient vs...
2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#19
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/29179998/ell2-regulates-dna-non-homologous-end-joining-nhej-repair-in-prostate-cancer-cells
#20
Yachen Zang, Laura E Pascal, Yibin Zhou, Xiaonan Qiu, Leizhen Wei, Junkui Ai, Joel B Nelson, Mingming Zhong, Boxin Xue, Shaoxiong Wang, Dongrong Yang, Li Lan, Yuxi Shan, Zhou Wang
ELL2 is an androgen-responsive gene that is expressed by prostate epithelial cells and is frequently down-regulated in prostate cancer. Deletion of Ell2 in the murine prostate induced murine prostatic intraepithelial neoplasia and ELL2 knockdown enhanced proliferation and migration in C4-2 prostate cancer cells. Here, knockdown of ELL2 sensitized prostate cancer cells to DNA damage and overexpression of ELL2 protected prostate cancer cells from DNA damage. Knockdown of ELL2 impaired non-homologous end joining repair but not homologous recombination repair...
February 28, 2018: Cancer Letters
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