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"Genomic integration"

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https://www.readbyqxmd.com/read/28213501/immature-lymphocytes-inhibit-rag1-and-rag2-transcription-and-v-d-j-recombination-in-response-to-dna-double-strand-breaks
#1
Megan R Fisher, Adrian Rivera-Reyes, Noah B Bloch, David G Schatz, Craig H Bassing
Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double-strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ataxia telangiectasia mutated (ATM) kinase to feedback-inhibit RAG expression and RAG cleavage of the other Igκ allele...
February 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28208635/advances-in-non-viral-dna-vectors-for-gene-therapy
#2
Cinnamon L Hardee, Lirio Milenka Arévalo-Soliz, Benjamin D Hornstein, Lynn Zechiedrich
Uses of viral vectors have thus far eclipsed uses of non-viral vectors for gene therapy delivery in the clinic. Viral vectors, however, have certain issues involving genome integration, the inability to be delivered repeatedly, and possible host rejection. Fortunately, development of non-viral DNA vectors has progressed steadily, especially in plasmid vector length reduction, now allowing these tools to fill in specifically where viral or other non-viral vectors may not be the best options. In this review, we examine the improvements made to non-viral DNA gene therapy vectors, highlight opportunities for their further development, address therapeutic needs for which their use is the logical choice, and discuss their future expansion into the clinic...
February 10, 2017: Genes
https://www.readbyqxmd.com/read/28207814/jmjd-5-kdm8-regulates-h3k36me2-and-is-required-for-late-steps-of-homologous-recombination-and-genome-integrity
#3
Pier Giorgio Amendola, Nico Zaghet, João J Ramalho, Jens Vilstrup Johansen, Mike Boxem, Anna Elisabetta Salcini
The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination...
February 16, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28205273/in-vitro-responses-to-known-in-vivo-genotoxic-agents-in-mouse-germ-cells
#4
Khaled Habas, Martin H Brinkworth, Diana Anderson
Genotoxic compounds have induced DNA damage in male germ cells and have been associated with adverse clinical outcomes including enhanced risks for maternal, paternal and offspring health. DNA strand breaks represent a great threat to the genomic integrity of germ cells. Such integrity is essential to maintain spermatogenesis and prevent reproduction failure. The Comet assay results revealed that the incubation of isolated germ cells with n-ethyl-n-nitrosourea (ENU), 6-mercaptopurine (6-MP) and methyl methanesulphonate (MMS) led to increase in length of Olive tail moment and % tail DNA when compared with the untreated control cells and these effects were concentration-dependent...
February 16, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28204611/a-genome-integrated-massively-parallel-reporter-assay-reveals-dna-sequence-determinants-of-cis-regulatory-activity-in-neural-cells
#5
Brett B Maricque, Joseph D Dougherty, Barak A Cohen
No abstract text is available yet for this article.
February 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28202543/nucleosome-like-ssdna-histone-octamer-complexes-and-the-implication-for-dna-double-strand-break-repair
#6
Nicholas L Adkins, Sarah G Swygert, Parminder Kaur, Hengyao Niu, Sergei A Grigoryev, Patrick Sung, Hong Wang, Craig L Peterson
Repair of DNA double strand breaks (DSBs) is key for maintenance of genome integrity. When DSBs are repaired by homologous recombination, DNA ends can undergo extensive processing, producing long stretches of single-stranded DNA (ssDNA). In vivo, DSB processing occurs in the context of chromatin, and studies indicate that histones may remain associated with processed DSBs. Here we demonstrate that histones are not evicted from ssDNA after in vitro chromatin resection. In addition, we reconstitute histone-ssDNA complexes (termed ssNucs) with ssDNA and recombinant histones and analyze these particles by a combination of native gel electrophoresis, sedimentation velocity, electron microscopy, and a recently developed electrostatic force microscopy technique, DREEM (Dual-Resonance-frequency-Enhanced Electrostatic force Microscopy)...
February 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28199840/citron-kinase-deficiency-leads-to-chromosomal-instability-and-tp53-sensitive-microcephaly
#7
Federico Tommaso Bianchi, Chiara Tocco, Gianmarco Pallavicini, Yifan Liu, Fiammetta Vernì, Chiara Merigliano, Silvia Bonaccorsi, Nadia El-Assawy, Lorenzo Priano, Marta Gai, Gaia Elena Berto, Alessandra Maria Adelaide Chiotto, Francesco Sgrò, Alessia Caramello, Laura Tasca, Ugo Ala, Francesco Neri, Salvatore Oliviero, Alessandro Mauro, Stephan Geley, Maurizio Gatti, Ferdinando Di Cunto
Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28199214/base-excision-repair-of-oxidative-dna-damage-from-mechanism-to-disease
#8
Amy M Whitaker, Matthew A Schaich, Mallory S Smith, Tony S Flynn, Bret D Freudenthal
Reactive oxygen species continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. Both oxidative DNA damage itself and its repair mediate the progression of many prevalent human maladies. The major pathway tasked with removal of oxidative DNA damage, and hence maintaining genomic integrity, is base excision repair (BER). The aphorism that structure often dictates function has proven true, as numerous recent structural biology studies have aided in clarifying the molecular mechanisms used by key BER enzymes during the repair of damaged DNA...
March 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28197536/proteomics-reveals-a-new-dna-repair-factor-involved-in-dna-damage-signaling
#9
Markus Räschle
Stalling of the DNA replication machinery activates the ATR checkpoint kinase, which coordinates the cellular responses to replication stress. New studies identify a novel ATR activator, ETAA1, which is indispensable for the maintenance of genome integrity. Dysregulation of ETAA1 may contribute to the development of pancreatic cancer.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28193840/co-chaperone-hsp70-hsp90-organizing-protein-hop-is-required-for-transposon-silencing-and-pirna-biogenesis
#10
Joseph A Karam, Rasesh Y Parikh, Dhananjaya Nayak, David Rosenkranz, Vamsi K Gangaraju
piRNAs are 26-30nt germ-line specific small non-coding RNAs that have evolutionarily conserved function in mobile genetic element (transposons) silencing and maintenance of genome integrity. Drosophila Hsp70/90 Organizing Protein Homolog (Hop), a co-chaperone, interacts with piRNA binding protein Piwi and mediates silencing of phenotypic variations. However, it is not known if Hop has a direct role in piRNA biogenesis and transposon silencing. Here, we show that knockdown of Hop in the germ-line nurse cells (GLKD) of Drosophila ovaries leads to activation of transposons...
February 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28192398/cyclind-cdk4-6-complexes-phosphorylate-cdc25a-and-regulate-its-stability
#11
C Dozier, L Mazzolini, C Cénac, C Froment, O Burlet-Schiltz, A Besson, S Manenti
The phosphatase CDC25A is a key regulator of cell cycle progression by dephosphorylating and activating cyclin-CDK complexes. CDC25A is an unstable protein expressed from G1 until mitosis. CDC25A overexpression, which can be caused by stabilization of the protein, accelerates the G1/S and G2/M transitions, leading to genomic instability and promoting tumorigenesis. Thus, controlling CDC25A protein levels by regulating its stability is a critical mechanism for timing cell cycle progression and to maintain genomic integrity...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28188246/cutting-edge-the-transcription-factor-sox2-regulates-aid-expression-in-class-switched-b-cells
#12
Lauren J DiMenna, Wei-Feng Yen, Laura Nicolas, Rahul Sharma, Zara N Saldanha, Jayanta Chaudhuri
IgH class switch recombination (CSR) occurs through the deliberate introduction of activation-induced cytidine deaminase (AID)-instigated DNA double-strand breaks into the IgH loci. Because double-strand breaks are generally highly toxic, mechanisms that regulate AID expression are of much relevance to CSR and genomic integrity; however, effectors of such regulatory processes are still poorly understood. In this article, we show that the transcription factor sex determining region Y-box 2 (Sox2) is expressed in activated B cells, but almost exclusively in those that have undergone CSR...
February 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28180282/ataxin-3-promotes-genome-integrity-by-stabilizing-chk1
#13
Yingfeng Tu, Hongmei Liu, Xuefei Zhu, Hongyan Shen, Xiaolu Ma, Fengli Wang, Min Huang, Juanjuan Gong, Xiaoling Li, Yun Wang, Caixia Guo, Tie-Shan Tang
No abstract text is available yet for this article.
February 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28177753/histone-h3-3-regulates-mitotic-progression-in-mouse-embryonic-fibroblasts
#14
Aysegul Ors, Christophe Papin, Bertrand Favier, Yohan Roulland, Defne Dalkara, Mehmet Ozturk, ALi Hamiche, Stefan Dimitrov, Kiran Padmanabhan
H3.3 is a histone variant, which marks transcription start sites as well as telomeres and heterochromatic sites on the genome. H3.3 presence is thought to positively correlate with transcriptional status of its target genes. Using a conditional genetic strategy against H3.3B combined with short hairpin RNAs against H3.3A, we essentially depleted all H3.3 gene expression in mouse embryonic fibroblasts. Following nearly complete loss of H3.3 in cells, our transcriptomic analyses show very little impact on global gene expression as well as on histone variant H2A...
February 1, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/28176872/genotoxic-effects-of-culture-media-on-human-pluripotent-stem-cells
#15
Megha Prakash Bangalore, Syama Adhikarla, Odity Mukherjee, Mitradas M Panicker
Culture conditions play an important role in regulating the genomic integrity of Human Pluripotent Stem Cells (HPSCs). We report that HPSCs cultured in Essential 8 (E8) and mTeSR, two widely used media for feeder-free culturing of HPSCs, had many fold higher levels of ROS and higher mitochondrial potential than cells cultured in Knockout Serum Replacement containing media (KSR). HPSCs also exhibited increased levels of 8-hydroxyguanosine, phospho-histone-H2a.X and p53, as well as increased sensitivity to γ-irradiation in these two media...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28174687/dicer-a-new-regulator-of-pluripotency-exit-and-line-1-elements-in-mouse-embryonic-stem-cells
#16
Maxime Bodak, Daniel Cirera-Salinas, Jian Yu, Richard P Ngondo, Constance Ciaudo
A gene regulation network orchestrates processes ensuring the maintenance of cellular identity and genome integrity. Small RNAs generated by the RNAse III DICER have emerged as central players in this network. Moreover, deletion of Dicer in mice leads to early embryonic lethality. To better understand the underlying mechanisms leading to this phenotype, we generated Dicer-deficient mouse embryonic stem cells (mESCs). Their detailed characterization revealed an impaired differentiation potential, and incapacity to exit from the pluripotency state...
February 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28174430/mitotic-spindle-assembly-in-animal-cells-a-fine-balancing-act
#17
REVIEW
Suzanna L Prosser, Laurence Pelletier
The mitotic spindle has a crucial role in ensuring the accurate segregation of chromosomes into the two daughter cells during cell division, which is paramount for maintaining genome integrity. It is a self-organized and dynamic macromolecular structure that is constructed from microtubules, microtubule-associated proteins and motor proteins. Thirty years of research have led to the identification of centrosome-, chromatin- and microtubule-mediated microtubule nucleation pathways that each contribute to mitotic spindle assembly...
February 8, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28167771/ipscs-and-fibroblast-subclones-from-the-same-fibroblast-population-contain-comparable-levels-of-sequence-variations
#18
Erika M Kwon, John P Connelly, Nancy F Hansen, Frank X Donovan, Thomas Winkler, Brian W Davis, Halah Alkadi, Settara C Chandrasekharappa, Cynthia E Dunbar, James C Mullikin, Paul Liu
Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs-whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28167048/biochemical-fractionation-of-time-resolved-drosophila-embryos-reveals-similar-transcriptomic-alterations-in-replication-checkpoint-and-histone-mrna-processing-mutants
#19
Fabio Alexis Lefebvre, Louis Philip Benoit Bouvrette, Julie Bergalet, Eric Lécuyer
In higher eukaryotes, maternally provided gene products drive the initial stages of embryogenesis until the zygotic transcriptional program takes over, a developmental process called the midblastula transition (MBT). In addition to zygotic genome activation, the MBT involves alterations in cell-cycle length and the implementation of DNA damage/replication checkpoints that serve to monitor genome integrity. Previous work has shown that mutations affecting histone mRNA metabolism or DNA replication checkpoint factors severely impact developmental progression through the MBT, prompting us to characterize and contrast the transcriptomic impact of these genetic perturbations...
February 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28166748/body-mass-index-modifies-the-relationship-between-%C3%AE-h2ax-a-dna-damage-biomarker-and-pathological-complete-response-in-triple-negative-breast-cancer
#20
Maddalena Barba, Patrizia Vici, Laura Pizzuti, Luigi Di Lauro, Domenico Sergi, Anna Di Benedetto, Cristiana Ercolani, Francesca Sperati, Irene Terrenato, Claudio Botti, Lucia Mentuccia, Laura Iezzi, Teresa Gamucci, Clara Natoli, Ilio Vitale, Marcella Mottolese, Ruggero De Maria, Marcello Maugeri-Saccà
BACKGROUND: Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). Overweight and obesity are linked to a variety of pathways regulating tumor-promoting functions, including the DNA damage response (DDR). The DDR physiologically safeguards genome integrity but, in a neoplastic background, it is aberrantly engaged and protects cancer cells from chemotherapy. We herein verified the role of BMI on a previously assessed association between DDR biomarkers and pathological complete response (pCR) in TNBC patients treated with neoadjuvant chemotherapy (NACT)...
February 6, 2017: BMC Cancer
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