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NHEJ pathway

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https://www.readbyqxmd.com/read/29330493/development-of-versatile-non-homologous-end-joining-based-knock-in-module-for-genome-editing
#1
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
#2
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
#3
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/29298990/gsk3%C3%AE-negatively-regulates-trax-a-scaffold-protein-implicated-in-mental-disorders-for-nhej-mediated-dna-repair-in-neurons
#4
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
#5
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
#6
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
#7
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
#8
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/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#9
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/29227966/pot1-inhibits-the-efficiency-but-promotes-the-fidelity-of-nonhomologous-end-joining-at-non-telomeric-dna-regions
#10
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
#11
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
#12
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/29217771/rad52-is-required-for-rna-templated-recombination-repair-in-post-mitotic-neurons
#13
Starr Welty, Yaqun Teng, Zhuobin Liang, Weixing Zhao, Laurie Sanders, J Timothy Greenamyre, Maria Eulalia Rubio, Amantha Thathiah, Ravindra Kodali, Ronald Wetzel, Arthur S Levine, Li Lan
It has been long assumed that post-mitotic neurons only utilize the error-prone non-homologous end joining (NHEJ) pathway to repair double strand breaks (DSBs) associated with oxidative damage to DNA, given the inability of non-replicating neuronal DNA to utilize a sister chromatid template in the less error-prone homologous recombination (HR) repair pathway. However, we and others recently have found that active transcription triggers a replication-independent recombinational repair mechanism in the G0/G1 phase of the cell cycle...
December 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29210569/modulating-dna-repair-pathways-to-improve-precision-genome-engineering
#14
Katherine S Pawelczak, Navnath S Gavande, Pamela S VanderVere-Carozza, John J Turchi
Programmable nucleases like the popular CRISPR/Cas9 system allow for precision genome engineering by inducing a site-specific DNA double strand break (DSB) within a genome. The DSB is repaired by endogenous DNA repair pathways, either non-homologous end joining (NHEJ) or homology directed repair (HDR). The predominant and error-prone NHEJ pathway often results in small nucleotide insertions or deletions that can be used to construct knockout alleles. Alternatively, HDR activity can result in precise modification incorporating exogenous DNA fragments into the cut site...
December 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29204698/fumarase-is-involved-in-dna-double-strand-break-resection-through-a-functional-interaction-with-sae2
#15
Michael Leshets, Dharanidharan Ramamurthy, Michael Lisby, Norbert Lehming, Ophry Pines
One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs...
December 4, 2017: Current Genetics
https://www.readbyqxmd.com/read/29191918/pml-nuclear-body-disruption-cooperates-in-apl-pathogenesis-and-impairs-dna-damage-repair-pathways-in-mice
#16
Edwige Voisset, Eva Moravcsik, Eva W Stratford, Amie Jaye, Christopher J Palgrave, Robert K Hills, Paolo Salomoni, Scott C Kogan, Ellen Solomon, David Grimwade
A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of PML nuclear bodies (NBs) mediated by the PML-RARα oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by two point mutations (C62A/C65A) in the Pml RING domain. While no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period...
November 30, 2017: Blood
https://www.readbyqxmd.com/read/29190394/acetylation-of-53bp1-dictates-the-dna-double-strand-break-repair-pathway
#17
Xiang Guo, Yongtai Bai, Meimei Zhao, Mei Zhou, Qinjian Shen, Cai-Hong Yun, Hongquan Zhang, Wei-Guo Zhu, Jiadong Wang
P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruited to sites of DSBs via recognition of H4K20me2 through the Tudor-UDR domain and H2AK15ub through the UDR motif. Although extensive studies have been conducted, it remains unclear how the post-translational modification of 53BP1 affects DSB repair pathway choice...
November 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29188477/crispr-cas9-mediated-efficient-editing-in-phytoene-desaturase-pds-demonstrates-precise-manipulation-in-banana-cv-rasthali-genome
#18
Navneet Kaur, Anshu Alok, Shivani, Navjot Kaur, Pankaj Pandey, Praveen Awasthi, Siddharth Tiwari
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has been reported for precise genome modification in many plants. In the current study, we demonstrate a successful mutation in phytoene desaturase (RAS-PDS) of banana cv. Rasthali using the CRISPR/Cas9 system. Two PDS genes were isolated from Rasthali (RAS-PDS1 and RAS-PDS2), and their protein sequence analysis confirmed that both PDS comprises conserved motifs for enzyme activity. Phylogenetic analysis of RAS-PDS1 and RAS-PDS2 revealed a close evolutionary relationship with other monocot species...
November 29, 2017: Functional & Integrative Genomics
https://www.readbyqxmd.com/read/29176614/inhibition-of-53bp1-favors-homology-dependent-dna-repair-and-increases-crispr-cas9-genome-editing-efficiency
#19
Marella D Canny, Nathalie Moatti, Leo C K Wan, Amélie Fradet-Turcotte, Danielle Krasner, Pedro A Mateos-Gomez, Michal Zimmermann, Alexandre Orthwein, Yu-Chi Juang, Wei Zhang, Sylvie M Noordermeer, Eduardo Seclen, Marcus D Wilson, Andrew Vorobyov, Meagan Munro, Andreas Ernst, Timothy F Ng, Tiffany Cho, Paula M Cannon, Sachdev S Sidhu, Frank Sicheri, Daniel Durocher
Programmable nucleases, such as Cas9, are used for precise genome editing by homology-dependent repair (HDR). However, HDR efficiency is constrained by competition from other double-strand break (DSB) repair pathways, including non-homologous end-joining (NHEJ). We report the discovery of a genetically encoded inhibitor of 53BP1 that increases the efficiency of HDR-dependent genome editing in human and mouse cells. 53BP1 is a key regulator of DSB repair pathway choice in eukaryotic cells and functions to favor NHEJ over HDR by suppressing end resection, which is the rate-limiting step in the initiation of HDR...
November 27, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29171825/guardians-of-the-mycobacterial-genome-a-review-on-dna-repair-systems-in-mycobacterium-tuberculosis
#20
Amandeep Singh
The genomic integrity of Mycobacterium tuberculosis is continuously threatened by the harsh survival conditions inside host macrophages, due to immune and antibiotic stresses. Faithful genome maintenance and repair must be accomplished under stress for the bacillus to survive in the host, necessitating a robust DNA repair system. The importance of DNA repair systems in pathogenesis is well established. Previous examination of the M. tuberculosis genome revealed homologues of almost all the major DNA repair systems, i...
November 24, 2017: Microbiology
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