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https://www.readbyqxmd.com/read/28589393/a-history-of-genome-editing-in-mammals
#1
Almudena Fernández, Santiago Josa, Lluis Montoliu
Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation...
June 6, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/28512351/non-homologous-dna-end-joining-and-alternative-pathways-to-double-strand-break-repair
#2
REVIEW
Howard H Y Chang, Nicholas R Pannunzio, Noritaka Adachi, Michael R Lieber
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. In all mammalian cells, DSBs that occur throughout the cell cycle are repaired predominantly by the non-homologous DNA end joining (NHEJ) pathway. Defects in NHEJ result in sensitivity to ionizing radiation and the ablation of lymphocytes. The NHEJ pathway utilizes proteins that recognize, resect, polymerize and ligate the DNA ends in a flexible manner. This flexibility permits NHEJ to function on a wide range of DNA-end configurations, with the resulting repaired DNA junctions often containing mutations...
May 17, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28498430/uva-induced-upregulation-of-progerin-suppresses-53bp1%C3%A2-mediated-nhej-dsb-repair-in-human-keratinocytes-via-progerin-lamin%C3%A2-a-complex-formation
#3
Xin Huang, Yun Pan, Di Cao, Sheng Fang, Kun Huang, Jin Chen, Aijun Chen
Ultraviolet (UV) radiation is the primary risk factor underlying photoaging and photocarcinogenesis. Mounting research has focused on the role of DNA damage response pathways in UV-induced double-strand break (DSB) repair. In the present study, we hypothesized that UVA-induced aberrant progerin upregulation may adversely affect p53-binding protein 1 (53BP1)-mediated non-homologous end joining (NHE) DSB repair in human keratinocytes. Basal cell carcinoma (BCC) tumors and matching normal skin tissue were sampled (n=200) to investigate whether human keratinocytes display dysregulated progerin expression as a function of advancing age and BCC status...
April 26, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28431013/dna-double-strand-break-repair-in-penaeus-monodon-is-predominantly-dependent-on-homologous-recombination
#4
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/28336179/control-of-dna-end-resection-by-yeast-hmo1p-affects-efficiency-of-dna-end-joining
#5
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/28278729/genomic-instability-is-a-principle-pathologic-feature-of-flt3-itd-kinase-activity-in-acute-myeloid-leukemia-leading-to-clonal-evolution-and-disease-progression
#6
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...
September 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28258155/doxorubicin-and-vincristine-affect-undifferentiated-rat-spermatogonia
#7
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
#8
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) after aberrant dsDNA repair via the endogenous non-homology end-joining (NHEJ) pathway or, alternatively, for enhancing homology-directed repair 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 activity...
April 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28216226/nbs1-phosphorylation-status-dictates-repair-choice-of-dysfunctional-telomeres
#9
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/28177771/precision-genome-editing-in-the-crispr-era
#10
REVIEW
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...
April 2017: 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/28119335/dna-double-strand-break-repair-in-penaeus-monodon-is-predominantly-dependent-on-homologous-recombination
#12
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/28057860/contribution-of-canonical-nonhomologous-end-joining-to-chromosomal-rearrangements-is-enhanced-by-atm-kinase-deficiency
#13
Ragini Bhargava, Caree R Carson, Gabriella Lee, Jeremy M Stark
A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal double-strand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Along these lines, we have tested whether the DNA damage response mediated by the Ataxia Telangiectasia Mutated (ATM) kinase may affect the relative influence of C-NHEJ vs...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27956611/biasing-genome-editing-events-toward-precise-length-deletions-with-an-rna-guided-tevcas9-dual-nuclease
#14
Jason M Wolfs, Thomas A Hamilton, Jeremy T Lant, Marcon Laforet, Jenny Zhang, Louisa M Salemi, Gregory B Gloor, Caroline Schild-Poulter, David R Edgell
The CRISPR/Cas9 nuclease is commonly used to make gene knockouts. The blunt DNA ends generated by cleavage can be efficiently ligated by the classical nonhomologous end-joining repair pathway (c-NHEJ), regenerating the target site. This repair creates a cycle of cleavage, ligation, and target site regeneration that persists until sufficient modification of the DNA break by alternative NHEJ prevents further Cas9 cutting, generating a heterogeneous population of insertions and deletions typical of gene knockouts...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27922005/wrn-regulates-pathway-choice-between-classical-and-alternative-non-homologous-end-joining
#15
Raghavendra A Shamanna, Huiming Lu, Jessica K de Freitas, Jane Tian, Deborah L Croteau, Vilhelm A Bohr
Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27869160/pot1-ob-fold-mutations-unleash-telomere-instability-to-initiate-tumorigenesis
#16
P Gu, Y Wang, K K Bisht, L Wu, L Kukova, E M Smith, Y Xiao, S M Bailey, M Lei, J Nandakumar, S Chang
Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear...
April 6, 2017: Oncogene
https://www.readbyqxmd.com/read/27806302/telomere-internal-double-strand-breaks-are-repaired-by-homologous-recombination-and-parp1-lig3-dependent-end-joining
#17
Ylli Doksani, Titia de Lange
Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27766006/genome-editing-in-large-animals
#18
James West, W Warren Gill
Genome editing in large animals has tremendous practical applications, from more accurate models for medical research through improved animal welfare and production efficiency. Although genetic modification in large animals has a 30 year history, until recently technical issues limited its utility. The original methods - pronuclear injection and integrating viruses - were plagued with problems associated with low efficiency, silencing, poor regulation of gene expression, and variability associated with random integration...
June 2016: Journal of Equine Veterinary Science
https://www.readbyqxmd.com/read/27701075/a-double-strand-break-can-trigger-immunoglobulin-gene-conversion
#19
Giulia Bastianello, Hiroshi Arakawa
All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system-gene conversion, somatic hypermutation and class switch recombination-require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease...
January 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27634057/cdk1-phosphorylates-wrn-at-collapsed-replication-forks
#20
Valentina Palermo, Sara Rinalducci, Massimo Sanchez, Francesca Grillini, Joshua A Sommers, Robert M Brosh, Lello Zolla, Annapaola Franchitto, Pietro Pichierri
Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability...
September 16, 2016: Nature Communications
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