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microhomology mediated end join

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https://www.readbyqxmd.com/read/29121353/secondary-structure-forming-sequences-drive-sd-mmej-repair-of-dna-double-strand-breaks
#1
Varandt Y Khodaverdian, Terrence Hanscom, Amy Marie Yu, Taylor L Yu, Victoria Mak, Alexander J Brown, Steven A Roberts, Mitch McVey
Alternative end-joining (alt-EJ) repair of DNA double-strand breaks is associated with deletions, chromosome translocations, and genome instability. Alt-EJ frequently uses annealing of microhomologous sequences to tether broken ends. When accessible pre-existing microhomologies do not exist, we have postulated that new microhomologies can be created via limited DNA synthesis at secondary-structure forming sequences. This model, called synthesis-dependent microhomology-mediated end joining (SD-MMEJ), predicts that differences between DNA sequences near double-strand breaks should alter repair outcomes in predictable ways...
November 7, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29116362/homologous-recombination-mediated-repair-of-dna-double-strand-breaks-operates-in-mammalian-mitochondria
#2
Sumedha Dahal, Shubham Dubey, Sathees C Raghavan
Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen...
November 7, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29073611/genomic-characterization-of-chromosomal-insertions-insights-into-the-mechanisms-underlying-chromothripsis
#3
Takema Kato, Yuya Ouchi, Hidehito Inagaki, Yoshio Makita, Seiji Mizuno, Mitsuharu Kajita, Toshiro Ikeda, Kazuhiro Takeuchi, Hiroki Kurahashi
Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations...
October 27, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28985340/genome-wide-mapping-of-large-deletions-and-their-population-genetic-properties-in-dairy-cattle
#4
Md Mesbah-Uddin, Bernt Guldbrandtsen, Terhi Iso-Touru, Johanna Vilkki, Dirk-Jan De Koning, Didier Boichard, Mogens Sandø Lund, Goutam Sahana
Large genomic deletions are potential candidate for loss-of-function, which could be lethal as homozygote. Analysing whole genome data of 175 cattle, we report 8,480 large deletions (199 bp-773 KB) with an overall false discovery rate of 8.8%; 82% of which are novel compared with deletions in the dbVar database. Breakpoint sequence analyses revealed that majority (24 of 29 tested) of the deletions contain microhomology/homology at breakpoint, and therefore, most likely generated by microhomology-mediated end joining...
September 8, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28754468/microhomology-mediated-end-joining-good-bad-and-ugly
#5
REVIEW
Ja-Hwan Seol, Eun Yong Shim, Sang Eun Lee
DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ)...
July 16, 2017: Mutation Research
https://www.readbyqxmd.com/read/28643258/crispr-cas9-mediated-targeted-knockin-of-exogenous-reporter-genes-in-zebrafish
#6
Atsuo Kawahara
Genome editing technologies such as ZFN, TALEN, and CRISPR/Cas9 efficiently induce DNA double-stranded breaks (DSBs) at a targeted genomic locus, often resulting in a frameshift-mediated target gene disruption. It remains difficult to perform targeted integration of exogenous genes by genome editing technologies. DSBs can be restored through DNA repair mechanisms, such as non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination (HR). It is well known that HR facilitates homology-dependent integration of donor DNA template into a targeted locus...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28634159/a-role-for-the-nonsense-mediated-mrna-decay-pathway-in-maintaining-genome-stability-in-caenorhabditis-elegans
#7
Víctor González-Huici, Bin Wang, Anton Gartner
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper-sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways...
August 2017: Genetics
https://www.readbyqxmd.com/read/28542210/drosophila-dna-polymerase-theta-utilizes-both-helicase-like-and-polymerase-domains-during-microhomology-mediated-end-joining-and-interstrand-crosslink-repair
#8
Kelly Beagan, Robin L Armstrong, Alice Witsell, Upasana Roy, Nikolai Renedo, Amy E Baker, Orlando D Schärer, Mitch McVey
Double strand breaks (DSBs) and interstrand crosslinks (ICLs) are toxic DNA lesions that can be repaired through multiple pathways, some of which involve shared proteins. One of these proteins, DNA Polymerase θ (Pol θ), coordinates a mutagenic DSB repair pathway named microhomology-mediated end joining (MMEJ) and is also a critical component for bypass or repair of ICLs in several organisms. Pol θ contains both polymerase and helicase-like domains that are tethered by an unstructured central region. While the role of the polymerase domain in promoting MMEJ has been studied extensively both in vitro and in vivo, a function for the helicase-like domain, which possesses DNA-dependent ATPase activity, remains unclear...
May 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28527830/crispr-cas9-mediated-precise-targeted-integration-in-vivo-using-a-double-cut-donor-with-short-homology-arms
#9
Xuan Yao, Xing Wang, Junlai Liu, Xinde Hu, Linyu Shi, Xiaowen Shen, Wenqin Ying, Xinyao Sun, Xin Wang, Pengyu Huang, Hui Yang
Precisely targeted genome editing is highly desired for clinical applications. However, the widely used homology-directed repair (HDR)-based genome editing strategies remain inefficient for certain in vivo applications. We here demonstrate a microhomology-mediated end-joining (MMEJ)-based strategy for precisely targeted gene integration in transfected neurons and hepatocytes in vivo with efficiencies up to 20%, much higher (up to 10 fold) than HDR-based strategy in adult mouse tissues. As a proof of concept of its therapeutic potential, we demonstrate the efficacy of MMEJ-based strategy in correction of Fah mutation and rescue of Fah(-/-) liver failure mice, offering an efficient approach for precisely targeted gene therapies...
June 2017: EBioMedicine
https://www.readbyqxmd.com/read/28524166/homology-mediated-end-joining-based-targeted-integration-using-crispr-cas9
#10
Xuan Yao, Xing Wang, Xinde Hu, Zhen Liu, Junlai Liu, Haibo Zhou, Xiaowen Shen, Yu Wei, Zijian Huang, Wenqin Ying, Yan Wang, Yan-Hong Nie, Chen-Chen Zhang, Sanlan Li, Leping Cheng, Qifang Wang, Yan Wu, Pengyu Huang, Qiang Sun, Linyu Shi, Hui Yang
Targeted integration of transgenes can be achieved by strategies based on homologous recombination (HR), microhomology-mediated end joining (MMEJ) or non-homologous end joining (NHEJ). The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining (HMEJ)-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and ∼800 bp of homology arms, and the targeted genome...
June 2017: Cell Research
https://www.readbyqxmd.com/read/28453368/establishment-of-expanded-and-streamlined-pipeline-of-pitch-knock-in-a-web-based-design-tool-for-mmej-mediated-gene-knock-in-pitch-designer-and-the-variations-of-pitch-pitch-tg-and-pitch-kiko
#11
Kazuki Nakamae, Yuki Nishimura, Mitsumasa Takenaga, Shota Nakade, Naoaki Sakamoto, Hiroshi Ide, Tetsushi Sakuma, Takashi Yamamoto
The emerging genome editing technology has enabled the creation of gene knock-in cells easily, efficiently, and rapidly, which has dramatically accelerated research in the field of mammalian functional genomics, including in humans. We recently developed a microhomology-mediated end-joining-based gene knock-in method, termed the PITCh system, and presented various examples of its application. Since the PITCh system only requires very short microhomologies (up to 40 bp) and single-guide RNA target sites on the donor vector, the targeting construct can be rapidly prepared compared with the conventional targeting vector for homologous recombination-based knock-in...
May 4, 2017: Bioengineered
https://www.readbyqxmd.com/read/28431013/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...
April 1, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28419093/microhomology-mediated-end-joining-induces-hypermutagenesis-at-breakpoint-junctions
#13
Supriya Sinha, Fuyang Li, Diana Villarreal, Jae Hoon Shim, Suhyeon Yoon, Kyungjae Myung, Eun Yong Shim, Sang Eun Lee
Microhomology (MH) flanking a DNA double-strand break (DSB) drives chromosomal rearrangements but its role in mutagenesis has not yet been analyzed. Here we determined the mutation frequency of a URA3 reporter gene placed at multiple locations distal to a DSB, which is flanked by different sizes (15-, 18-, or 203-bp) of direct repeat sequences for efficient repair in budding yeast. Induction of a DSB accumulates mutations in the reporter gene situated up to 14-kb distal to the 15-bp MH, but more modestly to those carrying 18- and 203-bp or no homology...
April 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28396487/culture-time-of-vitrified-warmed-zygotes-before-microinjection-affects-the-production-efficiency-of-crispr-cas9-mediated-knock-in-mice
#14
Yoshiko Nakagawa, Tetsushi Sakuma, Norihisa Nishimichi, Yasuyuki Yokosaki, Toru Takeo, Naomi Nakagata, Takashi Yamamoto
Robust reproductive engineering techniques are required for the efficient and rapid production of genetically modified mice. We have reported the efficient production of genome-edited mice using reproductive engineering techniques, such as ultra-superovulation, in vitro fertilization (IVF) and vitrification/warming of zygotes. We usually use vitrified/warmed fertilized oocytes created by IVF for microinjection because of work efficiency and flexible scheduling. Here, we investigated whether the culture time of zygotes before microinjection influences the efficiency of producing knock-in mice...
May 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28334774/high-tolerance-to-self-targeting-of-the-genome-by-the-endogenous-crispr-cas-system-in-an-archaeon
#15
Aris-Edda Stachler, Israela Turgeman-Grott, Ella Shtifman-Segal, Thorsten Allers, Anita Marchfelder, Uri Gophna
CRISPR-Cas systems allow bacteria and archaea to acquire sequence-specific immunity against selfish genetic elements such as viruses and plasmids, by specific degradation of invader DNA or RNA. However, this involves the risk of autoimmunity if immune memory against host DNA is mistakenly acquired. Such autoimmunity has been shown to be highly toxic in several bacteria and is believed to be one of the major costs of maintaining these defense systems. Here we generated an experimental system in which a non-essential gene, required for pigment production and the reddish colony color, is targeted by the CRISPR-Cas I-B system of the halophilic archaeon Haloferax volcanii...
May 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28292918/nonhomologous-end-joining-with-minimal-sequence-loss-is-promoted-by-the-mre11-rad50-nbs1-ctp1-complex-in-schizosaccharomyces-pombe
#16
Yanhui Li, Jinyu Wang, Gang Zhou, Michael Lajeunesse, Nga Le, Brittany N Stawicki, Yalitza Lopez Corcino, Kathleen L Berkner, Kurt W Runge
While the Mre11-Rad50-Nbs1 (MRN) complex has known roles in repair processes like homologous recombination and microhomology-mediated end-joining, its role in nonhomologous end-joining (NHEJ) is unclear as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and mammals have different requirements for repairing cut DNA ends. Most double-strand breaks (DSBs) require nucleolytic processing prior to DNA ligation. Therefore, we studied repair using the Hermes transposon, whose excision leaves a DSB capped by hairpin ends similar to structures generated by palindromes and trinucleotide repeats...
May 2017: Genetics
https://www.readbyqxmd.com/read/28272984/exogenous-gene-integration-mediated-by-genome-editing-technologies-in-zebrafish
#17
REVIEW
Hitoshi Morita, Kiyohito Taimatsu, Kanoko Yanagi, Atsuo Kawahara
Genome editing technologies, such as transcription activator-like effector nuclease (TALEN) and the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems, can induce DNA double-strand breaks (DSBs) at the targeted genomic locus, leading to frameshift-mediated gene disruption in the process of DSB repair. Recently, the technology-induced DSBs followed by DSB repairs are applied to integrate exogenous genes into the targeted genomic locus in various model organisms...
May 4, 2017: Bioengineered
https://www.readbyqxmd.com/read/28265068/cas9-mediated-genome-editing-in-the-methanogenic-archaeon-methanosarcina-acetivorans
#18
Dipti D Nayak, William W Metcalf
Although Cas9-mediated genome editing has proven to be a powerful genetic tool in eukaryotes, its application in Bacteria has been limited because of inefficient targeting or repair; and its application to Archaea has yet to be reported. Here we describe the development of a Cas9-mediated genome-editing tool that allows facile genetic manipulation of the slow-growing methanogenic archaeon Methanosarcina acetivorans Introduction of both insertions and deletions by homology-directed repair was remarkably efficient and precise, occurring at a frequency of approximately 20% relative to the transformation efficiency, with the desired mutation being found in essentially all transformants examined...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28253503/xp22-31-microdeletion-due-to-microhomology-mediated-break-induced-replication-in-a-boy-with-contiguous-gene-deletion-syndrome
#19
Koki Nagai, Hirohito Shima, Miki Kamimura, Junko Kanno, Erina Suzuki, Akira Ishiguro, Satoshi Narumi, Shigeo Kure, Ikuma Fujiwara, Maki Fukami
The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22...
2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28244221/genomic-rearrangements-induced-by-unscheduled-dna-double-strand-breaks-in-somatic-mammalian-cells
#20
REVIEW
Ayeong So, Tangui Le Guen, Bernard S Lopez, Josée Guirouilh-Barbat
DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to profound genome rearrangements and/or cell death. They routinely occur in genomes due to endogenous or exogenous stresses. Efficient repair systems, canonical non-homologous end-joining and homologous recombination exist in the cell and not only ensure the maintenance of genome integrity but also, via specific programmed DNA double-strand breaks, permit its diversity and plasticity. However, these repair systems need to be tightly controlled because they can also generate genomic rearrangements...
August 2017: FEBS Journal
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