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NHEJ pathway

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https://www.readbyqxmd.com/read/28336179/control-of-dna-end-resection-by-yeast-hmo1p-affects-efficiency-of-dna-end-joining
#1
Arvind Panday, LiJuan Xiao, Ashish Gupta, Anne Grove
The primary pathways for DNA double strand break (DSB) repair are homologous recombination (HR) and non-homologous end-joining (NHEJ). The choice between HR and NHEJ is influenced by the extent of DNA end resection, as extensive resection is required for HR but repressive to NHEJ. Conversely, association of the DNA end-binding protein Ku, which is integral to classical NHEJ, inhibits resection. In absence of key NHEJ components, a third repair pathway is exposed; this alternative-end joining (A-EJ) is a highly error-prone process that uses micro-homologies at the breakpoints and is initiated by DNA end resection...
March 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28331416/dna-pk-inhibition-by-nu7441-enhances-chemosensitivity-to-topoisomerase-inhibitor-in-non-small-cell-lung-carcinoma-cells-by-blocking-dna-damage-repair
#2
Masaaki Yanai, Haruhiko Makino, Bingqiong Ping, Kenichi Takeda, Natsumi Tanaka, Tomohiro Sakamoto, Kosuke Yamaguchi, Masahiro Kodani, Akira Yamasaki, Tadashi Igishi, Eiji Shimizu
BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells...
March 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/28278729/genomic-instability-is-a-principle-pathologic-feature-of-flt3-itd-kinase-activity-in-acute-myeloid-leukemia-leading-to-clonal-evolution-and-disease-progression
#3
Melanie T Rebechi, Keith W Pratz
Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double-strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways...
February 6, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28278048/brca1-recruitment-to-damaged-dna-sites-is-dependent-on-cdk9
#4
Thales C Nepomuceno, Vanessa C Fernandes, Thiago T Gomes, Renato S Carvalho, Guilherme Suarez-Kurtz, Alvaro N Monteiro, Marcelo A Carvalho
Double strand break lesions, the most toxic type of DNA damage, are repaired primarily through 2 distinct pathways: homology-directed recombination (HR) and non-homologous end-joining (NHEJ). BRCA1 and 53BP1, 2 proteins containing the BRCT modular domain, play an important role in DNA damage response (DDR) by orchestrating the decision between HR and NHEJ, but the precise mechanisms regarding both pathways are not entirely understood. Previously, our group identified a putative interaction between BRCA1 and BARD1 (BRCA1-associated RING domain 1) and the cyclin-dependent kinase (CDK9)...
February 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28258155/doxorubicin-and-vincristine-affect-undifferentiated-rat-spermatogonia
#5
Hermance Beaud, Ans M M van Pelt, Géraldine Delbes
Anticancer drugs such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. But less is known about their potential genotoxicity on SSC. Moreover, DNA repair mechanisms in SSC are poorly understood. To model treatments deprived of alkylating agents that are commonly used in cancer treatment, we tested the impact of exposure to doxorubicin and vincristine, alone or in combination (MIX), on a rat spermatogonial cell line with SSC characteristics (GC-6spg)...
March 3, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28228480/a-stable-but-reversible-integrated-surrogate-reporter-for-assaying-crispr-cas9-stimulated-homology-directed-repair
#6
Yahong Wen, Grace Liao, Thomas Pritchard, Ting-Ting Zhao, Jon P Connelly, Shondra M Pruett-Miller, Valerie Blanc, Nicholas O Davidson, Blair B Madison
The discovery and application of CRISPR/Cas9 technology for genome editing has greatly accelerated targeted mutagenesis in a variety of organisms. CRISPR/Cas9-mediated site-specific cleavage is typically exploited for the generation of insertions or deletions (indels) following aberrant dsDNA repair via the endogenous non-homology end-joining (NHEJ) pathway, or alternatively, for enhancing homology directed repair (HDR) to facilitate the generation of a specific mutation (or knock-in). However, there is a need for efficient cellular assays that can measure Cas9/guide RNA (gRNA) activity...
February 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28216226/nbs1-phosphorylation-status-dictates-repair-choice-of-dysfunctional-telomeres
#7
Rekha Rai, Chunyi Hu, Cayla Broton, Yong Chen, Ming Lei, Sandy Chang
Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2(TRFH) domain...
February 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28211448/cx-5461-is-a-dna-g-quadruplex-stabilizer-with-selective-lethality-in-brca1-2-deficient-tumours
#8
Hong Xu, Marco Di Antonio, Steven McKinney, Veena Mathew, Brandon Ho, Nigel J O'Neil, Nancy Dos Santos, Jennifer Silvester, Vivien Wei, Jessica Garcia, Farhia Kabeer, Daniel Lai, Priscilla Soriano, Judit Banáth, Derek S Chiu, Damian Yap, Daniel D Le, Frank B Ye, Anni Zhang, Kelsie Thu, John Soong, Shu-Chuan Lin, Angela Hsin Chin Tsai, Tomo Osako, Teresa Algara, Darren N Saunders, Jason Wong, Jian Xian, Marcel B Bally, James D Brenton, Grant W Brown, Sohrab P Shah, David Cescon, Tak W Mak, Carlos Caldas, Peter C Stirling, Phil Hieter, Shankar Balasubramanian, Samuel Aparicio
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks...
February 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28186989/inhibiting-dna-pkcs-in-a-non-homologous-end-joining-pathway-in-response-to-dna-double-strand-breaks
#9
Jun Dong, Tian Zhang, Yufeng Ren, Zhenyu Wang, Clifton C Ling, Fuqiu He, Gloria C Li, Chengtao Wang, Bixiu Wen
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28177771/precision-genome-editing-in-the-crispr-era
#10
Jayme Salsman, Graham Dellaire
With the introduction of precision genome editing using CRISPR-Cas9 technology, we have entered a new era of genetic engineering and gene therapy. With RNA-guided endonucleases, such as Cas9, it is possible to engineer DNA double strand breaks (DSB) at specific genomic loci. DSB repair by the error-prone non-homologous end-joining (NHEJ) pathway can disrupt a target gene by generating insertions and deletions. Alternatively, Cas9-mediated DSBs can be repaired by homology-directed repair (HDR) using an homologous DNA repair template, thus allowing precise gene editing by incorporating genetic changes into the repair template...
September 29, 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/28176781/rad52-competes-with-ku70-ku86-for-binding-to-s-region-dsb-ends-to-modulate-antibody-class-switch-dna-recombination
#11
Hong Zan, Connie Tat, Zhifang Qiu, Julia R Taylor, Justin A Guerrero, Tian Shen, Paolo Casali
Antibody class-switch DNA recombination (CSR) is initiated by AID-introduced DSBs in the switch (S) regions targeted for recombination, as effected by Ku70/Ku86-mediated NHEJ. Ku-deficient B cells, however, undergo (reduced) CSR through an alternative(A)-NHEJ pathway, which introduces microhomologies in S-S junctions. As microhomology-mediated end-joining requires annealing of single-strand DNA ends, we addressed the contribution of single-strand annealing factors HR Rad52 and translesion DNA polymerase θ to CSR...
February 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28163277/cloning-localization-and-focus-formation-at-dna-damage-sites-of-canine-ku70
#12
Manabu Koike, Yasutomo Yutoku, Aki Koike
Understanding the molecular mechanisms of DNA double-strand break (DSB) repair machinery, specifically non-homologous DNA-end joining (NHEJ), is crucial for developing next-generation radiotherapies and common chemotherapeutics for human and animal cancers. The localization, protein-protein interactions and post-translational modifications of core NHEJ factors, might play vital roles for regulation of NHEJ activity. The human Ku heterodimer (Ku70/Ku80) is a core NHEJ factor in the NHEJ pathway and is involved in sensing of DSBs...
February 6, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/28154079/dna-pkcs-structure-suggests-an-allosteric-mechanism-modulating-dna-double-strand-break-repair
#13
Bancinyane L Sibanda, Dimitri Y Chirgadze, David B Ascher, Tom L Blundell
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation...
February 3, 2017: Science
https://www.readbyqxmd.com/read/28133776/non-homologous-end-joining-common-interaction-sites-and-exchange-of-multiple-factors-in-the-dna-repair-process
#14
Stuart L Rulten, Gabrielle J Grundy
Non-homologous end-joining (NHEJ) is the dominant means of repairing chromosomal DNA double strand breaks (DSBs), and is essential in human cells. Fifteen or more proteins can be involved in the detection, signalling, synapsis, end-processing and ligation events required to repair a DSB, and must be assembled in the confined space around the DNA ends. We review here a number of interaction points between the core NHEJ components (Ku70, Ku80, DNA-PKcs, XRCC4 and Ligase IV) and accessory factors such as kinases, phosphatases, polymerases and structural proteins...
March 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28125611/lung-basal-stem-cells-rapidly-repair-dna-damage-using-the-error-prone-nonhomologous-end-joining-pathway
#15
Clare E Weeden, Yunshun Chen, Stephen B Ma, Yifang Hu, Georg Ramm, Kate D Sutherland, Gordon K Smyth, Marie-Liesse Asselin-Labat
Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage...
January 2017: PLoS Biology
https://www.readbyqxmd.com/read/28119335/dna-double-strand-break-repair-in-penaeus-monodon-is-predominantly-dependent-on-homologous-recombination
#16
Shikha Srivastava, Sumedha Dahal, Sharanya J Naidu, Deepika Anand, Vidya Gopalakrishnan, Rajendran Kooloth Valappil, Sathees C Raghavan
DNA double-strand breaks (DSBs) are mostly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR) in higher eukaryotes. In contrast, HR-mediated DSB repair is the major double-strand break repair pathway in lower order organisms such as bacteria and yeast. Penaeus monodon, commonly known as black tiger shrimp, is one of the economically important crustaceans facing large-scale mortality due to exposure to infectious diseases. The animals can also get exposed to chemical mutagens under the culture conditions as well as in wild...
January 24, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28118392/creation-of-novel-protein-variants-with-crispr-cas9-mediated-mutagenesis-turning-a-screening-by-product-into-a-discovery-tool
#17
Katherine F Donovan, Mudra Hegde, Meagan Sullender, Emma W Vaimberg, Cory M Johannessen, David E Root, John G Doench
CRISPR/Cas9 screening has proven to be a versatile tool for genomics research. Based on unexpected results from a genome-wide screen, we developed a CRISPR/Cas9-mediated approach to mutagenesis, exploiting the allelic diversity generated by error-prone non-homologous end-joining (NHEJ) to identify novel gain-of-function and drug resistant alleles of the MAPK signaling pathway genes MEK1 and BRAF. We define the parameters of a scalable technique to easily generate cell populations containing thousands of endogenous allelic variants to map gene functions...
2017: PloS One
https://www.readbyqxmd.com/read/28118114/coordination-of-the-ser2056-and-thr2609-clusters-of-dna-pkcs-in-regulating-gamma-rays-and-extremely-low-fluencies-of-alpha-particle-irradiation-to-g0-g1-phase-cells
#18
Hatsumi Nagasawa, Yu-Fen Lin, Takamitsu A Kato, John R Brogan, Hung-Ying Shih, Akihiro Kurimasa, Joel S Bedford, Benjamin P C Chen, John B Little
The catalytic subunit of DNA dependent protein kinase (DNA-PKcs) and its kinase activity are critical for mediation of non-homologous end-joining (NHEJ) of DNA double-strand breaks (DSB) in mammalian cells after gamma-ray irradiation. Additionally, DNA-PKcs phosphorylations at the T2609 cluster and the S2056 cluster also affect DSB repair and cellular sensitivity to gamma radiation. Previously we reported that phosphorylations within these two regions affect not only NHEJ but also homologous recombination repair (HRR) dependent DSB repair...
February 2017: Radiation Research
https://www.readbyqxmd.com/read/28114701/-genome-editing-tools-and-their-application-in-experimental-ophthalmology
#19
M Yanik, W Wende, K Stieger
New genome editing tools in molecular biology are revolutionising precise genome surgery and have greatly influenced experimental ophthalmology too. Aside from the commonly used nuclease-based platforms, such as the zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN), CRISPR/Cas systems, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes, perform very efficiently in site-specific DNA cleavage within living cells. DNA double strand breaks (DSB) are repaired through two different conserved repair pathways: NHEJ (non-homologous end joining) and HDR (homology directed repair)...
January 23, 2017: Klinische Monatsblätter Für Augenheilkunde
https://www.readbyqxmd.com/read/28096467/mir-21-mediated-radioresistance-occurs-via-promoting-repair-of-dna-double-strand-breaks
#20
Baocheng Hu, Xiang Wang, Shuofeng Hu, Xiaomin Ying, Ping Wang, Xiangming Zhang, Jian Wang, Hongyan Wang, Ya Wang
miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting GSK3B (a novel target of miR-21), which affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity...
February 24, 2017: Journal of Biological Chemistry
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