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NHEJ pathway

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https://www.readbyqxmd.com/read/29784639/tyrosine-kinase-inhibitor-induced-defects-in-dna-repair-sensitize-flt3-itd-positive-leukemia-cells-to-parp1-inhibitors
#1
Silvia Maifrede, Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, Zhaorui Lian, Elizaveta A Belyaeva, Alina Nersesyan, Marcin M Machnicki, Monika Toma, Nicolas Chatain, Malgorzata Rydzanicz, Huaqing Zhao, Jaroslav Jelinek, Katarzyna Piwocka, Tomasz Sliwinski, Tomasz Stoklosa, Rafal Ploski, Thomas Fischer, Stephen M Sykes, Steffen Koschmieder, Lars Bullinger, Peter Valent, Mariusz Wasik, Jian Huang, Tomasz Skorski
Mutations in the FMS-like tyrosine-kinase 3 (FLT3) such as internal tandem duplications (ITD) can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i), which are rarely curative. PARP1 inhibitors (PARP1i) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency...
May 21, 2018: Blood
https://www.readbyqxmd.com/read/29778533/casein-kinase-ii-phosphorylates-the-c-terminal-region-of-lif1-to-promote-the-lif1-xrs2-interaction-needed-for-non-homologous-end-joining
#2
Kenichiro Matsuzaki, Miki Shinohara
A DNA double strand break (DSB) is one of the most cytotoxic DNA lesions, but it can be repaired by non-homologous end joining (NHEJ) or by homologous recombination. The choice between these two repair pathways depends on the cell cycle stage. Although NHEJ constitutes a simple re-ligation reaction, the regulatory mechanism(s) controlling its activity has not been fully characterized. Lif1 is a regulatory subunit of the NHEJ-specific DNA ligase IV and interacts with Xrs2 of the MRX complex which is a key factor in DSB repair...
May 17, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29770864/agrobacterium-mediated-transformation-of-yeast-and-fungi
#3
Paul J J Hooykaas, G Paul H van Heusden, Xiaolei Niu, M Reza Roushan, Jalal Soltani, Xiaorong Zhang, Bert J van der Zaal
Two decades ago, it was discovered that the well-known plant vector Agrobacterium tumefaciens can also transform yeasts and fungi when these microorganisms are co-cultivated on a solid substrate in the presence of a phenolic inducer such as acetosyringone. It is important that the medium has a low pH (5-6) and that the temperature is kept at room temperature (20-25 °C) during co-cultivation. Nowadays, Agrobacterium-mediated transformation (AMT) is the method of choice for the transformation of many fungal species; as the method is simple, the transformation efficiencies are much higher than with other methods, and AMT leads to single-copy integration much more frequently than do other methods...
May 17, 2018: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/29769340/the-htlv-1-basic-leucine-zipper-factor-hbz-attenuates-repair-of-double-stranded-dna-breaks-via-non-homologous-end-joining-nhej
#4
A W Rushing, K Hoang, N Polakowski, I Lemasson
Adult T-cell leukemia (ATL) is a fatal malignancy of CD4+ T-cells infected with human T-cell leukemia virus type I (HTLV-1). ATL cells often exhibit random gross chromosomal rearrangements that are associated with the induction and improper repair of double-stranded DNA breaks (DSBs). The viral oncoprotein Tax has been reported to impair DSB repair, but is not shown to be consistently expressed throughout all phases of infection. The viral oncoprotein HTLV-1 basic leucine zipper factor (HBZ) is consistently expressed prior to and throughout disease progression, but it is unclear whether it also influences DSB repair...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29760279/histone-h3k27-methylation-is-required-for-nhej-and-genome-stability-by-modulating-the-dynamics-of-fancd2-on-chromatin
#5
Ye Zhang, Jian-Feng Chang, Jin Sun, Lu Chen, Xiao-Mei Yang, Huan-Yin Tang, Yuan-Ya Jing, Xuan Kang, Zhi-Min He, Jun-Yu Wu, Hui-Min Wei, Da-Liang Wang, Rong-Gang Xu, Rui-Bao Zhu, Ying Shen, Shi-Yang Zeng, Chen Wang, Kui-Nan Liu, Yong Zhang, Zhi-Ying Mao, Ci-Zhong Jiang, Fang-Lin Sun
Dysregulation of homeostatic balance in di- and tri-methyl H3K27 levels or that caused by mis-sense mutations of histone H3 (H3K27M) was reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in DIPG patients, dramatically attenuated the presence of 53BP1 foci and NHEJ repair capability in HDF cells. H3.1K27M cells showed increased rates of genomic insertions/deletions (In/Dels) and copy number variations (CNVs), as well as augmented p53-dependent apoptotic cells...
May 14, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29751014/a-versatile-tool-for-the-quantification-of-crispr-cas9-induced-genome-editing-events-in-human-hematopoietic-cell-lines-and-hematopoietic-stem-progenitor-cells
#6
Rajeswari Jayavaradhan, Devin Pillis, Punam Malik
The efficient site-specific DNA double-strand breaks (DSB) created by CRISPR/Cas9 has revolutionized genome engineering, and has great potential for editing hematopoietic stem/progenitor cells (HSPC). However, detailed understanding of the variables that influence choice of DNA-DSB repair (DDR) pathways by HSPC is required for therapeutic levels of editing in these clinically relevant cells. We developed a hematopoietic-reporter system that rapidly quantifies the three major DDR pathways utilized at the individual DSB created by CRISPR/Cas9: NHEJ, MMEJ and HDR; and show its applicability in evaluating the different DDR outcomes utilized by human hematopoietic cell lines and primary human HSPC...
May 8, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29739874/pten-regulates-non-homologous-end-joining-by-epigenetic-induction-of-nhej1-xlf
#7
Parker L Sulkowski, Susan E Scanlon, Sebastian Oeck, Peter M Glazer
DNA double-strand breaks (DSBs) are the most cytotoxic DNA lesions, and up to 90% of DSBs require repair by non-homologous end joining (NHEJ). Functional and genomic analyses of patient-derived melanomas revealed that PTEN loss is associated with NHEJ deficiency. In PTEN-null melanomas PTEN complementation rescued the NHEJ defect; conversely suppression of PTEN compromised NHEJ. Mechanistic studies revealed that PTEN promotes NHEJ through direct induction of expression of XRCC4-like factor (NHEJ1/XLF) which functions in DNA end bridging and ligation...
May 8, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29686104/interdependent-and-separable-functions-of-caenorhabditis-elegans-mrn-c-complex-members-couple-formation-and-repair-of-meiotic-dsbs
#8
Chloe Girard, Baptiste Roelens, Karl A Zawadzki, Anne M Villeneuve
Faithful inheritance of genetic information through sexual reproduction relies on the formation of crossovers between homologous chromosomes during meiosis, which, in turn, relies on the formation and repair of numerous double-strand breaks (DSBs). As DSBs pose a potential threat to the genome, mechanisms that ensure timely and error-free DSB repair are crucial for successful meiosis. Here, we identify NBS-1, the Caenorhabditis elegans ortholog of the NBS1 (mutated in Nijmegen Breakage Syndrome) subunit of the conserved MRE11-RAD50-NBS1/Xrs2 (MRN) complex, as a key mediator of DSB repair via homologous recombination (HR) during meiosis...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29685705/genistein-sensitizes-glioblastoma-cells-to-carbon-ions-via-inhibiting-dna-pkcs-phosphorylation-and-subsequently-repressing-nhej-and-delaying-hr-repair-pathways
#9
Xiongxiong Liu, Ping Li, Ryoichi Hirayama, Yuzhen Niu, Xinguo Liu, Weiqiang Chen, Xiaodong Jin, Pengcheng Zhang, Fei Ye, Ting Zhao, Bingtao Liu, Qiang Li
BACKGROUND AND PURPOSE: Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions. MATERIALS AND METHODS: Human glioblastoma (GBM) cell lines with or without genistein pre-treatment were irradiated with high-LET carbon ions...
April 20, 2018: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/29683658/enhanced-biosynthesis-performance-of-heterologous-proteins-in-cho-k1-cells-using-crispr-cas9
#10
Wenpeng Wang, Wenyun Zheng, Fengzhi Hu, Xiujuan He, Dong Wu, Wenliang Zhang, Haipeng Liu, Xingyuan Ma
Chinese hamster ovary (CHO) cells are the famous expression system for industrial production of recombinant proteins, such as therapeutic antibodies. However, there retained still bottlenecks in protein quality and weakness in expression efficiency because of the intrinsic genetic properties of the cell. Here we have enhanced biosynthesis performance of heterologous proteins in CHO-K1 cell using CRISPR-Cas9 by editing the genome precisely with two genes for improving ER microenvironment and reinforcing anti-apoptotic ability...
April 23, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29658569/%C3%AE-%C3%A2-catenin-nuclear-translocation-induced-by-hif%C3%A2-1%C3%AE-overexpression-leads-to-the-radioresistance-of-prostate-cancer
#11
Yong Luo, Mingchuan Li, Xuemei Zuo, Spyridon P Basourakos, Jiao Zhang, Jiahui Zhao, Yili Han, Yunhua Lin, Yongxing Wang, Yongguang Jiang, Ling Lan
Hypoxia-inducible factor‑1α (HIF‑1α) is known to play crucial roles in tumor radioresistance; however, the molecular mechanisms responsible for the promotion of tumor radioresistance by HIF‑1α remain unclear. β‑catenin is known to be involved in the metastatic potential of prostate cancer (PCa). In this study, to investigate the role of HIF‑1α and β‑catenin in the radioresistance of PCa, two PCa cell lines, LNCaP and C4‑2B, were grouped as follows: Negative control (no treatment), HIF‑1α overexpression group (transfected with HIF‑1α overexpression plasmid) and β‑catenin silenced group (transfected with HIF‑1α plasmids and β‑catenin-shRNA)...
April 12, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29655920/suppressing-ku70-ku80-expression-elevates-homology-directed-repair-efficiency-in-primary-fibroblasts
#12
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/29618789/altered-dna-repair-an-early-pathogenic-pathway-in-alzheimer-s-disease-and-obesity
#13
Hao Yu, Fiona Edith Harrison, Fen Xia
Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5-6 month and 16-18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of γ-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively...
April 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29577652/preliminary-study-of-the-homologous-recombination-repair-pathway-in-mouse-spermatogonial-stem-cells
#14
W Le, L Qi, C Xu, Z Xiang, Z Mao, J Zhang, J Xu, D Wu
The present study was designed to detect DNA repair response through the homologous recombination pathway in mouse spermatogonial stem cells. Mouse spermatogonial stem cells (mSSCs) were obtained from the adult DBA/2 mouse testes by MACS sorting. mSSCs and mice animals were divided into four groups (30 min, 2, 24 h, control) and treated with ionizing irradiation while the control group received pseudo-irradiation. Proteins involved in the homologous recombination pathway (γH2AX, ATM, RAD51, CtIP, and RPA2) were assessed in mSSCs both in vitro and in vivo...
March 25, 2018: Andrology
https://www.readbyqxmd.com/read/29566071/improving-the-efficiency-of-homologous-recombination-by-chemical-and-biological-approaches-in-yarrowia-lipolytica
#15
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/29531807/nf-%C3%AE%C2%BAb-inhibition-by-dimethylaminoparthenolide-radiosensitizes-non-small-cell-lung-carcinoma-by-blocking-dna-double-strand-break-repair
#16
Peter V Deraska, Colin O'Leary, Hunter D Reavis, Shelby Labe, Tru-Khang Dinh, Jean-Bernard Lazaro, Christopher Sweeney, Alan D D'Andrea, David Kozono
Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization...
December 2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29527968/linp1-facilitates-dna-damage-repair-through-non-homologous-end-joining-nhej-pathway-and-subsequently-decreases-the-sensitivity-of-cervical-cancer-cells-to-ionizing-radiation
#17
Xuanxuan Wang, Hai Liu, Liming Shi, Xiaoli Yu, Yanjun Gu, Xiaonan Sun
LncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) is an lncRNA which promotes therapeutic resistance in triple-negative breast cancer (TNBC). However, the expression and function of LINP1 in cervical cancer is not yet well-understood. In this study, we evaluated the expression levels of LINP1 in tumor tissues and cell lines of cervical cancer. We found that LINP1 associates with NHEJ proteins (Ku80 and DNA-PKcs). LINP1 translocates from cytosol to nucleus in response to irradiation. In addition, LINP1 knockdown significantly increases the levels of cleaved caspase3 and PARP, leading to enhanced cell apoptosis after ionizing radiation (IR)...
2018: Cell Cycle
https://www.readbyqxmd.com/read/29523790/mrn-complex-dependent-recruitment-of-ubiquitylated-blm-helicase-to-dsbs-negatively-regulates-dna-repair-pathways
#18
Vivek Tripathi, Himanshi Agarwal, Swati Priya, Harish Batra, Priyanka Modi, Monica Pandey, Dhurjhoti Saha, Sathees C Raghavan, Sagar Sengupta
Mutations in BLM in Bloom Syndrome patients predispose them to multiple types of cancers. Here we report that BLM is recruited in a biphasic manner to annotated DSBs. BLM recruitment is dependent on the presence of NBS1, MRE11 and ATM. While ATM activity is essential for BLM recruitment in early phase, it is dispensable in late phase when MRE11 exonuclease activity and RNF8-mediated ubiquitylation of BLM are the key determinants. Interaction between polyubiquitylated BLM and NBS1 is essential for the helicase to be retained at the DSBs...
March 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29520062/the-h2b-deubiquitinase-usp22-promotes-antibody-class-switch-recombination-by-facilitating-non-homologous-end-joining
#19
Conglei Li, Thergiory Irrazabal, Clare C So, Maribel Berru, Likun Du, Evelyn Lam, Alexanda K Ling, Jennifer L Gommerman, Qiang Pan-Hammarström, Alberto Martin
Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in γH2AX and impairs the classical non-homologous end joining (c-NHEJ), affecting both V(D)J recombination and CSR...
March 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29511621/robust-dna-repair-in-paxx-deficient-mammalian-cells
#20
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
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