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microhomology mediated end join

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https://www.readbyqxmd.com/read/29749794/molecular-cytogenetics-guides-massively-parallel-sequencing-of-a-radiation-induced-chromosome-translocation-in-human-cells
#1
Michael N Cornforth, Pavana Anur, Nicholas Wang, Erin Robinson, F Andrew Ray, Joel S Bedford, Bradford D Loucas, Eli S Williams, Myron Peto, Paul Spellman, Rahul Kollipara, Ralf Kittler, Joe W Gray, Susan M Bailey
Chromosome rearrangements are large-scale structural variants that are recognized drivers of oncogenic events in cancers of all types. Cytogenetics allows for their rapid, genome-wide detection, but does not provide gene-level resolution. Massively parallel sequencing (MPS) promises DNA sequence-level characterization of the specific breakpoints involved, but is strongly influenced by bioinformatics filters that affect detection efficiency. We sought to characterize the breakpoint junctions of chromosomal translocations and inversions in the clonal derivatives of human cells exposed to ionizing radiation...
May 11, 2018: Radiation Research
https://www.readbyqxmd.com/read/29671068/intracellular-generation-of-single-strand-template-increases-the-knock-in-efficiency-by-combining-crispr-cas9-with-aav
#2
Qing Xiao, Taishan Min, Shuangping Ma, Lingna Hu, Hongyan Chen, Daru Lu
Targeted integration of transgenes facilitates functional genomic research and holds prospect for gene therapy. The established microhomology-mediated end-joining (MMEJ)-based strategy leads to the precise gene knock-in with easily constructed donor, yet the limited efficiency remains to be further improved. Here, we show that single-strand DNA (ssDNA) donor contributes to efficient increase of knock-in efficiency and establishes a method to achieve the intracellular linearization of long ssDNA donor. We identified that the CRISPR/Cas9 system is responsible for breaking double-strand DNA (dsDNA) of palindromic structure in inverted terminal repeats (ITRs) region of recombinant adeno-associated virus (AAV), leading to the inhibition of viral second-strand DNA synthesis...
April 18, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29625543/mechanisms-of-mitochondrial-dna-repair-in-mammals
#3
REVIEW
L A Zinovkina
Accumulation of mutations in mitochondrial DNA leads to the development of severe, currently untreatable diseases. The contribution of these mutations to aging and progress of neurodegenerative diseases is actively studied. Elucidation of DNA repair mechanisms in mitochondria is necessary for both developing approaches to the therapy of diseases caused by mitochondrial mutations and understanding specific features of mitochondrial genome functioning. Mitochondrial DNA repair systems have become a subject of extensive studies only in the last decade due to development of molecular biology methods...
March 2018: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/29507284/microhomology-assisted-scarless-genome-editing-in-human-ipscs
#4
Shin-Il Kim, Tomoko Matsumoto, Harunobu Kagawa, Michiko Nakamura, Ryoko Hirohata, Ayano Ueno, Maki Ohishi, Tetsushi Sakuma, Tomoyoshi Soga, Takashi Yamamoto, Knut Woltjen
Gene-edited induced pluripotent stem cells (iPSCs) provide relevant isogenic human disease models in patient-specific or healthy genetic backgrounds. Towards this end, gene targeting using antibiotic selection along with engineered point mutations remains a reliable method to enrich edited cells. Nevertheless, integrated selection markers obstruct scarless transgene-free gene editing. Here, we present a method for scarless selection marker excision using engineered microhomology-mediated end joining (MMEJ)...
March 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/29500182/ku-dna-end-binding-activity-promotes-repair-fidelity-and-influences-end-processing-during-nonhomologous-end-joining-in-saccharomyces-cerevisiae
#5
Charlene H Emerson, Christopher R Lopez, Albert Ribes-Zamora, Erica J Polleys, Christopher L Williams, Lythou Yeo, Jacques E Zaneveld, Rui Chen, Alison A Bertuch
The Ku heterodimer acts centrally in nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB). Saccharomyces cerevisiae Ku, like mammalian Ku, binds and recruits NHEJ factors to DSB ends. Consequently, NHEJ is virtually absent in yeast Ku null ( yku70 ∆ or yku80 ∆) strains. Previously, we unexpectedly observed imprecise NHEJ proficiency in a yeast Ku mutant with impaired DNA end-binding (DEB). However, how DEB impairment supported imprecise NHEJ was unknown. Here, we found imprecise NHEJ proficiency to be a feature of a panel of DEB-impaired Ku mutants and that DEB impairment resulted in a deficiency in precise NHEJ...
May 2018: Genetics
https://www.readbyqxmd.com/read/29472448/double-stranded-dna-break-polarity-skews-repair-pathway-choice-during-intrachromosomal-and-interchromosomal-recombination
#6
Alexanda K Ling, Clare C So, Michael X Le, Audrey Y Chen, Lisa Hung, Alberto Martin
Activation-induced cytidine deaminase (AID) inflicts DNA damage at Ig genes to initiate class switch recombination (CSR) and chromosomal translocations. However, the DNA lesions formed during these processes retain an element of randomness, and thus knowledge of the relationship between specific DNA lesions and AID-mediated processes remains incomplete. To identify necessary and sufficient DNA lesions in CSR, the Cas9 endonuclease and nickase variants were used to program DNA lesions at a greater degree of predictability than is achievable with conventional induction of CSR...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29458716/selection-is-required-for-efficient-cas9-mediated-genome-editing-in-fusarium-graminearum
#7
Donald M Gardiner, Kemal Kazan
Genome engineering using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated nucleases, such as Cas9 (CRISPR-associated protein 9), are revolutionising molecular biology. In this study, we established a Cas9-based genome editing system in Fusarium graminearum, a highly destructive fungal pathogen of cereal crops. Although the molecular toolkit of F. graminearum is well developed compared to other fungi, Cas9-mediated engineering offers a number of potential benefits, such as the ability to create marker free mutants in this species...
February 2018: Fungal Biology
https://www.readbyqxmd.com/read/29327130/main-steps-in-dna-double-strand-break-repair-an-introduction-to-homologous-recombination-and-related-processes
#8
REVIEW
Lepakshi Ranjha, Sean M Howard, Petr Cejka
DNA double-strand breaks arise accidentally upon exposure of DNA to radiation and chemicals or result from faulty DNA metabolic processes. DNA breaks can also be introduced in a programmed manner, such as during the maturation of the immune system, meiosis, or cancer chemo- or radiotherapy. Cells have developed a variety of repair pathways, which are fine-tuned to the specific needs of a cell. Accordingly, vegetative cells employ mechanisms that restore the integrity of broken DNA with the highest efficiency at the lowest cost of mutagenesis...
January 11, 2018: Chromosoma
https://www.readbyqxmd.com/read/29323295/alcohol-and-endogenous-aldehydes-damage-chromosomes-and-mutate-stem-cells
#9
Juan I Garaycoechea, Gerry P Crossan, Frédéric Langevin, Lee Mulderrig, Sandra Louzada, Fentang Yang, Guillaume Guilbaud, Naomi Park, Sophie Roerink, Serena Nik-Zainal, Michael R Stratton, Ketan J Patel
Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair...
January 11, 2018: Nature
https://www.readbyqxmd.com/read/29320763/a-de-novo-50-bp-gnas-intragenic-duplication-in-a-patient-with-pseudohypoparathyroidism-type-1a
#10
Erina Suzuki, Ryosuke Bo, Kaori Sue, Hiroyuki Awano, Tsutomu Ogata, Satoshi Narumi, Masayo Kagami, Shinichiro Sano, Maki Fukami
Germline intragenic mutations in the GNAS locus result in pseudohypoparathyroidism type 1a (PHP1a) and related conditions. Nearly half of the previously reported GNAS intragenic mutations were structural variants, including 3 tandem duplications of 12-25 bp. However, the precise mutation spectrum and the genomic basis of GNAS structural variants remain to be clarified. Here, we report a de novo 50-bp tandem duplication in GNAS (c.723_772dup50, p.Glu259Leufs*29) identified in a patient with typical clinical features of PHP1a...
2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29311308/dna-double-strand-break-response-factors-influence-end-joining-features-of-igh-class-switch-and-general-translocation-junctions
#11
Rohit A Panchakshari, Xuefei Zhang, Vipul Kumar, Zhou Du, Pei-Chi Wei, Jennifer Kao, Junchao Dong, Frederick W Alt
Ig heavy chain (IgH) class switch recombination (CSR) in B lymphocytes switches IgH constant regions to change antibody functions. CSR is initiated by DNA double-strand breaks (DSBs) within a donor IgH switch (S) region and a downstream acceptor S region. CSR is completed by fusing donor and acceptor S region DSB ends by classical nonhomologous end-joining (C-NHEJ) and, in its absence, by alternative end-joining that is more biased to use longer junctional microhomologies (MHs). Deficiency for DSB response (DSBR) factors, including ataxia telangiectasia-mutated (ATM) and 53BP1, variably impair CSR end-joining, with 53BP1 deficiency having the greatest impact...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29222170/imprecision-and-dna-break-repair-biased-towards-incompatible-end-joining-in-leukemia
#12
Franz Josef Gassner, Maria Schubert, Stefan Rebhandl, Karina Spandl, Nadja Zaborsky, Kemal Catakovic, Stephanie Blaimer, Daniel Hebenstreit, Richard Greil, Roland Geisberger
Cancer is a genetic disease caused by mutations and chromosomal abnormalities that contribute to uncontrolled cell growth. In addition, cancer cells can rapidly respond to conventional and targeted therapies by accumulating novel and often specific genetic lesions leading to acquired drug resistance and relapsing disease. In chronic lymphocytic leukemia (CLL), however, diverse chromosomal aberrations often occur. In many cases, improper repair of DNA double-strand breaks (DSB) is a major source for genomic abnormalities...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29215093/two-large-deletions-extending-beyond-either-end-of-the-rhd-gene-and-their-red-cell-phenotypes
#13
Kshitij Srivastava, David Alan Stiles, Franz Friedrich Wagner, Willy Albert Flegel
Only two partial deletions longer than 655 nucleotides had been reported for the RHD gene, constrained within the gene and causing DEL phenotypes. Using a combination of quantitative PCR and long-range PCR, we examined three distinct deletions affecting parts of the RHD gene in three blood donors. Their RHD nucleotide sequences and exact boundaries of the breakpoint regions were determined. DEL phenotypes were caused by a novel 18.4 kb deletion and a previously published 5.4 kb deletion of the RHD gene; a D-negative phenotype was caused by a novel 7...
January 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29168504/mechanism-of-tandem-duplication-formation-in-brca1-mutant-cells
#14
Nicholas A Willis, Richard L Frock, Francesca Menghi, Erin E Duffey, Arvind Panday, Virginia Camacho, E Paul Hasty, Edison T Liu, Frederick W Alt, Ralph Scully
Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Here we define the mechanism underlying this rearrangement signature. We show that, in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks...
November 30, 2017: Nature
https://www.readbyqxmd.com/read/29121353/secondary-structure-forming-sequences-drive-sd-mmej-repair-of-dna-double-strand-breaks
#15
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...
December 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29116362/homologous-recombination-mediated-repair-of-dna-double-strand-breaks-operates-in-mammalian-mitochondria
#16
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
#17
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...
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
#18
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
#19
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
#20
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
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