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https://www.readbyqxmd.com/read/28439991/melatonin-a-pleiotropic-molecule-that-modulates-dna-damage-response-and-repair-pathways
#1
REVIEW
Maryam Majidinia, Alireza Sadeghpour, Saeed Mehrzadi, Russel J Reiter, Nasrin Khatami, Bahman Yousefi
DNA repair is responsible for maintaining the integrity of the genome. Perturbations in the DNA repair pathways have been identified in several human cancers. Thus, compounds targeting DNA damage response (DDR) hold great promise in cancer therapy. A great deal of effort, in pursuit of new anticancer drugs, has been devoted to understanding the basic mechanisms and functions of the cellular DNA repair machinery. Melatonin, a widely-produced indoleamine in all organisms is associated with a reduced risk of cancer and has multiple regulatory roles on the different aspects of the DDR and DNA repair...
April 25, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28439853/crispr-cas-mediated-in-planta-gene-targeting
#2
Simon Schiml, Friedrich Fauser, Holger Puchta
The recent emergence of the CRISPR/Cas system has boosted the possibilities for precise genome engineering approaches throughout all kingdoms of life. The most common application for plants is targeted mutagenesis, whereby a Cas9-mediated DNA double-strand break (DSB) is repaired by mutagenic nonhomologous end joining (NHEJ). However, the site-specific alteration of a genomic sequence or integration of a transgene relies on the precise repair by homologous recombination (HR) using a suitable donor sequence: this poses a particular challenge in plants, as NHEJ is the preferred repair mechanism for DSBs in somatic tissue...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28431013/dna-double-strand-break-repair-in-penaeus-monodon-is-predominantly-dependent-on-homologous-recombination
#3
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...
April 1, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28426349/rna-binging-protein-rbm14-regulates-dissociation-and-association-of-non-homologous-end-joining-proteins
#4
Nicholas Simon, Ming Yuan, Mihoko Kai
Defects in DNA damage response (DDR) are associated with multiple diseases, including cancers and neurodegenerative disorders. Emerging evidence indicates involvement of RNA-binding proteins (RBPs) in DDR. However, functions of the RBPs in DDR pathways remain elusive. We have shown previously that the RNA-binding protein RBM14 is required for non-homologous end joining (NHEJ). Here we show that RBM14 is required for efficient recruitment of XRCC4 and XLF to chromatin and release of KU proteins from chromatin upon DNA damage...
April 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28425306/therapeutic-targeting-and-patient-selection-for-cancers-with-homologous-recombination-defects
#5
Francien Talens, Mathilde Jalving, Jourik A Gietema, Marcel A T M van Vugt
DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected. Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28423717/non-homologous-end-joining-induced-alterations-in-dna-methylation-a-source-of-permanent-epigenetic-change
#6
Brittany Allen, Antonio Pezone, Antonio Porcellini, Mark T Muller, Michal M Masternak
In addition to genetic mutations, epigenetic revision plays a major role in the development and progression of cancer; specifically, inappropriate DNA methylation or demethylation of CpG residues may alter the expression of genes that promote tumorigenesis. We hypothesize that DNA repair, specifically the repair of DNA double strand breaks (DSB) by Non-Homologous End Joining (NHEJ) may play a role in this process. Using a GFP reporter system inserted into the genome of HeLa cells, we are able to induce targeted DNA damage that enables the cells, after successfully undergoing NHEJ repair, to express WT GFP...
March 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418813/radiation-induced-deletions-in-mouse-spermatogonia-are-usually-large-over-200-kb-and-contain-little-sequence-similarity-at-the-junctions
#7
Mieko Kodaira, Jun-Ichi Asakawa, Nori Nakamura
Ionizing radiation can induce mutations, and the majority of radiation-induced mutations in mammalian cells are deletions. The most critical types of radiation-induced DNA damage are DNA double-strand breaks, and these breaks are repaired by either the homologous recombination (HR) pathway or the non-homologous end joining (NHEJ) pathway. The HR pathway is not as mutagenic as the NHEJ pathway, and it is expected that radiation-induced deletions would usually have little sequence similarity around the deletion junction points...
April 18, 2017: Radiation Research
https://www.readbyqxmd.com/read/28417998/marker-free-coselection-for-crispr-driven-genome-editing-in-human-cells
#8
Daniel Agudelo, Alexis Duringer, Lusiné Bozoyan, Caroline C Huard, Sophie Carter, Jeremy Loehr, Dafni Synodinou, Mathieu Drouin, Jayme Salsman, Graham Dellaire, Josée Laganière, Yannick Doyon
Targeted genome editing enables the creation of bona fide cellular models for biological research and may be applied to human cell-based therapies. Therefore, broadly applicable and versatile methods for increasing its efficacy in cell populations are highly desirable. We designed a simple and robust coselection strategy for enrichment of cells with either nuclease-driven nonhomologous end joining (NHEJ) or homology-directed repair (HDR) events by harnessing the multiplexing capabilities of CRISPR-Cas9 and Cpf1 systems...
April 17, 2017: Nature Methods
https://www.readbyqxmd.com/read/28398510/the-swi-snf-atp-dependent-nucleosome-remodeler-promotes-resection-initiation-at-a-dna-double-strand-break-in-yeast
#9
Nathaniel E Wiest, Scott Houghtaling, Joseph C Sanchez, Alan E Tomkinson, Mary Ann Osley
DNA double-strand breaks (DSBs) are repaired by either the non-homologous end joining (NHEJ) or homologous recombination (HR) pathway. Pathway choice is determined by the generation of 3΄ single-strand DNA overhangs at the break that are initiated by the action of the Mre11-Rad50-Xrs2 (MRX) complex to direct repair toward HR. DSB repair occurs in the context of chromatin, and multiple chromatin regulators have been shown to play important roles in the repair process. We have investigated the role of the SWI/SNF ATP-dependent nucleosome-remodeling complex in the repair of a defined DNA DSB...
April 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28393832/structural-insights-into-pot1-tpp1-interaction-and-pot1-c-terminal-mutations-in-human-cancer
#10
Cong Chen, Peili Gu, Jian Wu, Xianyun Chen, Shuangshuang Niu, Hong Sun, Lijie Wu, Na Li, Junhui Peng, Shaohua Shi, Cuiying Fan, Min Huang, Catherine C L Wong, Qingguo Gong, Chandan Kumar-Sinha, Rongguang Zhang, Lajos Pusztai, Rekha Rai, Sandy Chang, Ming Lei
Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα-β complex, POT1-TPP1 adopts an elongated V-shaped conformation...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28389334/loss-of-dusp3-activity-radiosensitizes-human-tumor-cell-lines-via-attenuation-of-dna-repair-pathways
#11
Thompson E P Torres, Lilian C Russo, Alexsandro Santos, Gabriela R Marques, Yuli T Magalhaes, Sartaj Tabassum, Fabio L Forti
BACKGROUND: Radiotherapy causes the regression of many human tumors by increasing DNA damage, and the novel molecular mechanisms underlying the genomic instability leading to cancer progression and metastasis must be elucidated. Atypical dual-specificity phosphatase 3 (DUSP3) has been shown to down-regulate mitogen-activated protein kinases (MAPKs) to control the proliferation and apoptosis of human cancer cells. We have recently identified novel molecular targets of DUSP3 that function in DNA damage response and repair; however, whether DUSP3 affects these processes remains unknown...
April 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28386301/new-traits-in-crops-produced-by-genome-editing-techniques-based-on-deletions
#12
REVIEW
C C M van de Wiel, J G Schaart, L A P Lotz, M J M Smulders
One of the most promising New Plant Breeding Techniques is genome editing (also called gene editing) with the help of a programmable site-directed nuclease (SDN). In this review, we focus on SDN-1, which is the generation of small deletions or insertions (indels) at a precisely defined location in the genome with zinc finger nucleases (ZFN), TALENs, or CRISPR-Cas9. The programmable nuclease is used to induce a double-strand break in the DNA, while the repair is left to the plant cell itself, and mistakes are introduced, while the cell is repairing the double-strand break using the relatively error-prone NHEJ pathway...
2017: Plant Biotechnology Reports
https://www.readbyqxmd.com/read/28383660/chd1-loss-sensitizes-prostate-cancer-to-dna-damaging-therapy-by-promoting-error-prone-double-strand-break-repair
#13
T R Shenoy, G Boysen, M Y Wang, Q Z Xu, W Guo, F M Koh, C Wang, L Z Zhang, Y Wang, V Gil, S Aziz, R Christova, D N Rodrigues, M Crespo, P Rescigno, N Tunariu, R Riisnaes, Z Zafeiriou, P Flohr, W Yuan, E Knight, A Swain, M Ramalho-Santos, D Y Xu, J de Bono, H Wu
BACKGROUND: Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. DESIGN: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines...
April 5, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28382286/non-homologous-end-joining-inhibitor-scr-7-to-exacerbate-low-dose-doxorubicin-cytotoxicity-in-hela-cells
#14
Ajay Kumar, Devyani Bhatkar, Devashree Jahagirdar, Nilesh Kumar Sharma
Among the genotoxic drug regimens, doxorubicin (DOX) is known for its high-dose side effects in several carcinomas, including cervical cancer. This study reports on testing the combined use of a DOX genotoxic drug and SCR-7 non-homologous end joining (NHEJ) inhibitor for HeLa cells. An in vitro DNA damaging assay of DOX was performed on plasmid and genomic DNA substrate. In vitro cytotoxicity was investigated using trypan blue dye exclusion, DNA metabolizing, and propidium iodide-based flow cytometric assays...
March 2017: Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28374058/control-of-gene-editing-by-manipulation-of-dna-repair-mechanisms
#15
Eric Danner, Sanum Bashir, Saniye Yumlu, Wolfgang Wurst, Benedikt Wefers, Ralf Kühn
DNA double-strand breaks (DSBs) are produced intentionally by RNA-guided nucleases to achieve genome editing through DSB repair. These breaks are repaired by one of two main repair pathways, classic non-homologous end joining (c-NHEJ) and homology-directed repair (HDR), the latter being restricted to the S/G2 phases of the cell cycle and notably less frequent. Precise genome editing applications rely on HDR, with the abundant c-NHEJ formed mutations presenting a barrier to achieving high rates of precise sequence modifications...
April 3, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/28369484/nbs1-is-regulated-by-two-kind-of-mechanisms-atm-dependent-complex-formation-with-mre11-and-rad50-and-cell-cycle-dependent-degradation-of-protein
#16
Hui Zhou, Kasumi Kawamura, Hiromi Yanagihara, Junya Kobayashi, Qiu-Mei Zhang-Akiyama
Nijmegen breakage syndrome (NBS), a condition similar to Ataxia-Telangiectasia (A-T), is a radiation-hypersensitive genetic disorder showing chromosomal instability, radio-resistant DNA synthesis, immunodeficiency, and predisposition to malignances. The product of the responsible gene, NBS1, forms a complex with MRE11 and RAD50 (MRN complex). The MRN complex is necessary for the DNA damage-induced activation of ATM. However, the regulation of MRN complex formation is still unclear. Here, we investigated the regulatory mechanisms of MRN complex formation...
March 22, 2017: Journal of Radiation Research
https://www.readbyqxmd.com/read/28361061/non-homologous-end-joining-protein-expression-screen-from-radiosensitive-cancer-patients-yields-a-novel-dna-double-strand-break-repair-phenotype
#17
Michael J McKay, Su Kak Goh, Jeremy N McKay, Michael Chao, Timothy M McKay
BACKGROUND: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. METHODS: We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis...
March 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28357369/functions-and-regulation-of-the-mrx-complex-at-dna-double-strand-breaks
#18
REVIEW
Elisa Gobbini, Corinne Cassani, Matteo Villa, Diego Bonetti, Maria P Longhese
DNA double-strand breaks (DSBs) pose a serious threat to genome stability and cell survival. Cells possess mechanisms that recognize DSBs and promote their repair through either homologous recombination (HR) or non-homologous end joining (NHEJ). The evolutionarily conserved Mre11-Rad50-Xrs2 (MRX) complex plays a central role in the cellular response to DSBs, as it is implicated in controlling end resection and in maintaining the DSB ends tethered to each other. Furthermore, it is responsible for DSB signaling by activating the checkpoint kinase Tel1 that, in turn, supports MRX function in a positive feedback loop...
July 27, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28336179/control-of-dna-end-resection-by-yeast-hmo1p-affects-efficiency-of-dna-end-joining
#19
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
#20
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
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