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Homologous recombination

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https://www.readbyqxmd.com/read/28346135/polo-like-kinase-dependent-phosphorylation-of-the-synaptonemal-complex-protein-syp-4-regulates-double-strand-break-formation-through-a-negative-feedback-loop
#1
Saravanapriah Nadarajan, Talley J Lambert, Elisabeth Altendorfer, Jinmin Gao, Michael D Blower, Jennifer C Waters, Monica P Colaiácovo
The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans...
March 27, 2017: ELife
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#2
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344992/mechanism-of-deletion-removing-all-dystrophin-exons-in-a-canine-model-for-dmd-implicates-concerted-evolution-of-x-chromosome-pseudogenes
#3
D Jake VanBelzen, Alock S Malik, Paula S Henthorn, Joe N Kornegay, Hansell H Stedman
Duchenne muscular dystrophy (DMD) is a lethal, X-linked, muscle-wasting disorder caused by mutations in the large, 2.4-Mb dystrophin gene. The majority of DMD-causing mutations are sporadic, multi-exon, frameshifting deletions, with the potential for variable immunological tolerance to the dystrophin protein from patient to patient. While systemic gene therapy holds promise in the treatment of DMD, immune responses to vectors and transgenes must first be rigorously evaluated in informative preclinical models to ensure patient safety...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344191/transposition-of-insertion-sequence-is256bsu1-in-bacillus-subtilis-168-is-strictly-dependent-on-reca
#4
Motohiro Akashi, Shota Harada, Syunsuke Moki, Yuki Okouji, Kiwamu Takahashi, Shigeki Kada, Keigo Yamagami, Yasuhiko Sekine, Satoru Watanabe, Taku Chibazakura, Hirofumi Yoshikawa
We developed an insertion sequence transposition detection system called the "jumping cat assay" and applied it to the Bacillus subtilis chromosome using IS256Bsu1 derived from B. subtilis natto. The high frequency of transposition enabled us to explore host factors; combining the assay and genetic analyses revealed that recA is essential for the transposition of IS256Bsu1. Detailed analyses using various domain mutants of recA demonstrated that this essentiality is not related to the function of recA in homologous recombination...
March 24, 2017: Genes & Genetic Systems
https://www.readbyqxmd.com/read/28341751/low-recombination-proficiency-score-rps-predicts-heightened-sensitivity-to-dna-damaging-chemotherapy-in-breast-cancer
#5
Sean Pitroda, Riyue Bao, Jorge Andrade, Ralph R Weichselbaum, Philip P Connell
PURPOSE: Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair. We hypothesized low RPS values can identify HR-deficient breast cancers most sensitive to DNA-damaging chemotherapy...
March 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28341648/dna-damage-tolerance-pathway-choice-through-uls1-modulation-of-srs2-sumoylation-in-saccharomyces-cerevisiae
#6
Karol Kramarz, Seweryn Mucha, Ireneusz Litwin, Anna Barg-Wojas, Robert Wysocki, Dorota Dziadkowiec
DNA damage tolerance and homologous recombination pathways function to bypass replication blocking lesions and ensure completion of DNA replication. However, inappropriate activation of these pathways may lead to increased mutagenesis or formation of deleterious recombination intermediates often leading to cell death or cancer formation in higher organisms. Posttranslational modifications of PCNA regulate the choice of repair pathways at replication forks. Its monoubiquitination favors translesion synthesis while polyubiquitination stimulates template switching...
March 24, 2017: Genetics
https://www.readbyqxmd.com/read/28339470/meiotic-recombination-modulates-the-structure-and-dynamics-of-the-synaptonemal-complex-during-c-elegans-meiosis
#7
Divya Pattabiraman, Baptiste Roelens, Alexander Woglar, Anne M Villeneuve
During meiotic prophase, a structure called the synaptonemal complex (SC) assembles at the interface between aligned pairs of homologous chromosomes, and crossover recombination events occur between their DNA molecules. Here we investigate the inter-relationships between these two hallmark features of the meiotic program in the nematode C. elegans, revealing dynamic properties of the SC that are modulated by recombination. We demonstrate that the SC incorporates new subunits and switches from a more highly dynamic/labile state to a more stable state as germ cells progress through the pachytene stage of meiotic prophase...
March 24, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28339300/genetic-manipulation-by-zinc-finger-nucleases-in-rat-induced-pluripotent-stem-cells
#8
Sheng Yang, Shufang Ding, Qianhua Xu, Xiong Li, Qiong Xiong
Induced pluripotent stem cells (iPSCs) have an extensive application in regenerative medicine, pharmaceutical discovery, and basic research. With the recent derivation of rat iPSCs, it is now feasible to apply genetic manipulation in this species. But such tools do not yet exist for many rat strains, especially for disease model rat. The Sprague Dawley (SD) rat is an inbred disease model for hypertension, nephropathy, pulmonary hypertension, depression, and alcohol consumption. In this study, the SD rat iPSCs were generated using lentiviral method...
March 24, 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28338736/microcompartmentation-of-cytosolic-aldolase-by-interaction-with-the-actin-cytoskeleton-in-arabidopsis
#9
Constantine Garagounis, Kalliopi-Ioanna Kostaki, Tim J Hawkins, Ian Cummins, Mark D Fricker, Patrick J Hussey, Alistair M Hetherington, Lee J Sweetlove
Evidence is accumulating for molecular microcompartments formed when proteins interact in localized domains with the cytoskeleton, organelle surfaces, and intracellular membranes. To understand the potential functional significance of protein microcompartmentation in plants, we studied the interaction of the glycolytic enzyme fructose bisphosphate aldolase with actin in Arabidopsis thaliana. Homology modelling of a major cytosolic isozyme of aldolase, FBA8, suggested that the tetrameric holoenzyme has two actin binding sites and could therefore act as an actin-bundling protein, as was reported for animal aldolases...
February 17, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/28337556/homologous-gene-targeting-of-a-carotenoids-biosynthetic-gene-in-rhodosporidium-toruloides-by-agrobacterium-mediated-transformation
#10
Wenyi Sun, Xiaobing Yang, Xueying Wang, Xinping Lin, Yanan Wang, Sufang Zhang, Yushi Luan, Zongbao K Zhao
OBJECTIVES: To target a carotenoid biosynthetic gene in the oleaginous yeast Rhodosporidium toruloides by using the Agrobacterium-mediated transformation (AMT) method. RESULTS: The RHTO_04602 locus of R. toruloides NP11, previously assigned to code the carotenoid biosynthetic gene CRTI, was amplified from genomic DNA and cloned into the binary plasmid pZPK-mcs, resulting in pZPK-CRT. A HYG-expression cassette was inserted into the CRTI sequence of pZPK-CRT by utilizing the restriction-free clone strategy...
March 23, 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/28336543/in-vivo-binding-of-prdm9-reveals-interactions-with-noncanonical-genomic-sites
#11
Corinne Grey, Julie A J Clément, Jérôme Buard, Benjamin Leblanc, Ivo Gut, Marta Gut, Laurent Duret, Bernard de Massy
In mouse and human meiosis, DNA double-strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence-specific DNA binding domain of the PRDM9 histone methyl transferase. Here, we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a noncanonical recruitment of PRDM9 to sites that lack recombination activity and the PRDM9 binding consensus motif. These sites include gene promoters, where PRDM9 is recruited in a DSB-dependent manner...
March 23, 2017: Genome Research
https://www.readbyqxmd.com/read/28336516/a-novel-role-of-the-dna2-translocase-function-in-dna-break-resection
#12
Adam S Miller, James M Daley, Nhung Tuyet Pham, Hengyao Niu, Xiaoyu Xue, Grzegorz Ira, Patrick Sung
DNA double-strand break repair by homologous recombination entails nucleolytic resection of the 5' strand at break ends. Dna2, a flap endonuclease with 5'-3' helicase activity, is involved in the resection process. The Dna2 helicase activity has been implicated in Okazaki fragment processing during DNA replication but is thought to be dispensable for DNA end resection. Unexpectedly, we found a requirement for the helicase function of Dna2 in end resection in budding yeast cells lacking exonuclease 1. Biochemical analysis reveals that ATP hydrolysis-fueled translocation of Dna2 on ssDNA facilitates 5' flap cleavage near a single-strand-double strand junction while attenuating 3' flap incision...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28336515/the-motor-activity-of-dna2-functions-as-an-ssdna-translocase-to-promote-dna-end-resection
#13
Maryna Levikova, Cosimo Pinto, Petr Cejka
DNA2 nuclease-helicase functions in DNA replication and recombination. This requires the nuclease of DNA2, while, in contrast, the role of the helicase activity has been unclear. We now show that the motor activity of both recombinant yeast and human DNA2 promotes efficient degradation of long stretches of ssDNA, particularly in the presence of the replication protein A. This degradation is further stimulated by a direct interaction with a cognate RecQ family helicase, which functions with DNA2 in DNA end resection to initiate homologous recombination...
March 23, 2017: Genes & Development
https://www.readbyqxmd.com/read/28336179/control-of-dna-end-resection-by-yeast-hmo1p-affects-efficiency-of-dna-end-joining
#14
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/28335590/roles-of-budding-yeast-hrr25-in-recombination-and-sporulation
#15
Min-Su Lee, Jeong Hwan Joo, Keunpil Kim
Hrr25, a casein kinase 1 δ/ε homolog in budding yeast, is essential to set up mono-orientation of sister kinetochores during meiosis. Hrr25 kinase activity coordinates sister chromatid cohesion via cohesin phosphorylation. Here, we investigated the prophase roles of Hrr25 using the auxin-inducible degron system and by ectopic expression of Hrr25 during yeast meiosis. Hrr25 mediates nuclear division in meiosis I but does not affect DNA replication. We also found that initiation of meiotic double-strand breaks as well as joint molecule formation were normal in HRR25-deficient cells...
March 24, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28335389/characteristics%C3%A2-and%C3%A2-lethality%C3%A2-of%C3%A2-a%C3%A2-novel%C3%A2-recombinant%C3%A2-dermonecrotic%C3%A2-venom%C3%A2-phospholipase%C3%A2-d%C3%A2-from%C3%A2-hemiscorpius%C3%A2-lepturus
#16
Elham Torabi, Mahdi Behdani, Mohammad Hosseininejad Chafi, Reza Moazzami, Jean-Marc Sabatier, Vahid Khalaj, Delavar Shahbazzadeh, Kamran Pooshang Bagheri
Hemoscorpius lepturus is the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation are remarkably similar to those reported for brown spiders, including dermonecrosis, hematuria, renal failure and even death. The lethality and toxicity of brown spiders' venom have been attributed to its phospholipase D activity. This study aims to identify a phospholipase D with possible lethality and dermonecrotic activity in H. lepturus venom. In this study, a cDNA library of the venom glands was generated by Illumina RNA sequencing...
March 13, 2017: Toxins
https://www.readbyqxmd.com/read/28334891/rad51-interconnects-between-dna-replication-dna-repair-and-immunity
#17
Souparno Bhattacharya, Kalayarasan Srinivasan, Salim Abdisalaam, Fengtao Su, Prithvi Raj, Igor Dozmorov, Ritu Mishra, Edward K Wakeland, Subroto Ghose, Shibani Mukherjee, Aroumougame Asaithamby
RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334759/highly-efficient-biallelic-genome-editing-of-human-es-ips-cells-using-a-crispr-cas9-or-talen-system
#18
Kazuo Takayama, Keisuke Igai, Yasuko Hagihara, Rina Hashimoto, Morifumi Hanawa, Tetsushi Sakuma, Masashi Tachibana, Fuminori Sakurai, Takashi Yamamoto, Hiroyuki Mizuguchi
Genome editing research of human ES/iPS cells has been accelerated by clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) and transcription activator-like effector nucleases (TALEN) technologies. However, the efficiency of biallelic genetic engineering in transcriptionally inactive genes is still low, unlike that in transcriptionally active genes. To enhance the biallelic homologous recombination efficiency in human ES/iPS cells, we performed screenings of accessorial genes and compounds...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28331098/recombinant-modified-vaccinia-virus-ankara-generating-ebola-virus-like-particles
#19
Marc Schweneker, Andrea S Laimbacher, Gert Zimmer, Susanne Wagner, Elisabeth M Schraner, Michael Wolferstätter, Marieken Klingenberg, Ulrike Dirmeier, Robin Steigerwald, Henning Lauterbach, Hubertus Hochrein, Paul Chaplin, Mark Suter, Jürgen Hausmann
There are currently no approved therapeutics or vaccines to treat or protect against the severe hemorrhagic fever and death caused by Ebola virus (EBOV). Ebola virus-like particles (EBOV-VLPs) consisting of the matrix protein VP40, the glycoprotein (GP) and the nucleoprotein (NP) are highly immunogenic and protective in non-human primates against Ebola virus disease (EVD). We have constructed a modified vaccinia virus Ankara-Bavarian Nordic(®) (MVA-BN(®)) recombinant co-expressing VP40 and glycoprotein (GP) of EBOV Mayinga and the nucleoprotein (NP) of Taï Forest virus (TAFV) (MVA-BN-EBOV-VLP) to launch non-infectious EBOV-VLPs as a second vaccine modality in the MVA-BN-EBOV-VLP-vaccinated organism...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28329681/sirt6-promotes-dna-end-joining-in-ipscs-derived-from-old-mice
#20
Wen Chen, Nana Liu, Hongxia Zhang, Haiping Zhang, Jing Qiao, Wenwen Jia, Songcheng Zhu, Zhiyong Mao, Jiuhong Kang
Induced pluripotent stem cells (iPSCs) have great potential for treating age-related diseases, but the genome integrity of iPSCs is critically important. Here, we demonstrate that non-homologous end joining (NHEJ), rather than homologous recombination (HR), is less efficient in iPSCs from old mice than young mice. We further find that Sirt6 is downregulated in iPSCs from old mice. Sirt6 directly binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus promoting DNA-PKcs phosphorylation at residue S2056, leading to efficient NHEJ...
March 21, 2017: Cell Reports
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