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"Genomic integration"

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https://www.readbyqxmd.com/read/27930667/protein-phosphatase-6-protects-prophase-i-arrested-oocytes-by-safeguarding-genomic-integrity
#1
Meng-Wen Hu, Tie-Gang Meng, Zong-Zhe Jiang, Ming-Zhe Dong, Heide Schatten, Xingzhi Xu, Zhen-Bo Wang, Qing-Yuan Sun
Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported that protein phosphatase 6 (PP6), a member of the PP2A-like subfamily, which accounts for cellular serine/threonine phosphatase activity, functions in completing the second meiosis. Here, we generated mutant mice with a specific deletion of Ppp6c in oocytes from the primordial follicle stage by crossing Ppp6cF/F mice with Gdf9-Cre mice and found that Ppp6cF/F; GCre+ mice are infertile...
December 8, 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27929021/host-genome-integration-and-giant-virus-induced-reactivation-of-the-virophage-mavirus
#2
Matthias G Fischer, Thomas Hackl
Endogenous viral elements are increasingly found in eukaryotic genomes, yet little is known about their origins, dynamics, or function. Here we provide a compelling example of a DNA virus that readily integrates into a eukaryotic genome where it acts as an inducible antiviral defence system. We found that the virophage mavirus, a parasite of the giant Cafeteria roenbergensis virus (CroV), integrates at multiple sites within the nuclear genome of the marine protozoan Cafeteria roenbergensis. The endogenous mavirus is structurally and genetically similar to eukaryotic DNA transposons and endogenous viruses of the Maverick/Polinton family...
December 7, 2016: Nature
https://www.readbyqxmd.com/read/27924017/a-genome-integrated-massively-parallel-reporter-assay-reveals-dna-sequence-determinants-of-cis-regulatory-activity-in-neural-cells
#3
Brett B Maricque, Joseph D Dougherty, Barak A Cohen
Recent large-scale genomics efforts to characterize the cis-regulatory sequences that orchestrate genome-wide expression patterns have produced impressive catalogues of putative regulatory elements. Most of these sequences have not been functionally tested, and our limited understanding of the non-coding genome prevents us from predicting which sequences are bona fide cis-regulatory elements. Recently, massively parallel reporter assays (MPRAs) have been deployed to measure the activity of putative cis-regulatory sequences in several biological contexts, each with specific advantages and distinct limitations...
October 23, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923845/numerical-and-spatial-patterning-of-yeast-meiotic-dna-breaks-by-tel1
#4
Neeman Mohibullah, Scott Keeney
The Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Mechanisms of this regulation remain poorly understood. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to reveal aspects of the contribution of the Saccharomyces cerevisiae DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM). A tel1Δ mutant has globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing...
December 6, 2016: Genome Research
https://www.readbyqxmd.com/read/27921283/choices-have-consequences-the-nexus-between-dna-repair-pathways-and-genomic-instability-in-cancer
#5
REVIEW
Sonali Bhattacharjee, Saikat Nandi
BACKGROUND: The genome is under constant assault from a multitude of sources that can lead to the formation of DNA double-stand breaks (DSBs). DSBs are cytotoxic lesions, which if left unrepaired could lead to genomic instability, cancer and even cell death. However, erroneous repair of DSBs can lead to chromosomal rearrangements and loss of heterozygosity, which in turn can also cause cancer and cell death. Hence, although the repair of DSBs is crucial for the maintenance of genome integrity the process of repair need to be well regulated and closely monitored...
December 2016: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/27919340/consequences-of-irradiation-on-adult-spermatogenesis-between-infertility-and-hereditary-risk
#6
Henri-Baptiste Marjault, Isabelle Allemand
DNA damage response in adult spermatogenic cells should limit the propagation of mutations to the offspring, without being detrimental to fertility. In differentiating spermatogenic cells, the genomic instability is limited in time, whereas in spermatogonial stem cells it can be maintained all along life. Spermatogonial stem cells are long-lived cells that support normal germ cell differentiation and must be preserved throughout life. However after irradiation spermatogenesis recovery can be impaired as a consequence of the radiation-induced decline in spermatogonial stem cell...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27916001/sirtuins-in-metabolism-dna-repair-and-cancer
#7
REVIEW
Zhen Mei, Xian Zhang, Jiarong Yi, Junjie Huang, Jian He, Yongguang Tao
The mammalian sirtuin family has attracted tremendous attention over the past few years as stress adaptors and post-translational modifier. They have involved in diverse cellular processes including DNA repair, energy metabolism, and tumorigenesis. Notably, genomic instability and metabolic reprogramming are two of characteristic hallmarks in cancer. In this review, we summarize current knowledge on the functions of sirtuins mainly regarding DNA repair and energy metabolism, and further discuss the implication of sirtuins in cancer specifically by regulating genome integrity and cancer-related metabolism...
December 5, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27906959/pcna-dependent-cleavage-and-degradation-of-sde2-regulates-response-to-replication-stress
#8
Ukhyun Jo, Winson Cai, Jingming Wang, Yoojin Kwon, Alan D D'Andrea, Hyungjin Kim
Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27905394/uvr2-ensures-transgenerational-genome-stability-under-simulated-natural-uv-b-in-arabidopsis-thaliana
#9
Eva-Maria Willing, Thomas Piofczyk, Andreas Albert, J Barbro Winkler, Korbinian Schneeberger, Ales Pecinka
Ground levels of solar UV-B radiation induce DNA damage. Sessile phototrophic organisms such as vascular plants are recurrently exposed to sunlight and require UV-B photoreception, flavonols shielding, direct reversal of pyrimidine dimers and nucleotide excision repair for resistance against UV-B radiation. However, the frequency of UV-B-induced mutations is unknown in plants. Here we quantify the amount and types of mutations in the offspring of Arabidopsis thaliana wild-type and UV-B-hypersensitive mutants exposed to simulated natural UV-B over their entire life cycle...
December 1, 2016: Nature Communications
https://www.readbyqxmd.com/read/27901072/characterisation-of-functional-domains-in-fission-yeast-ams2-that-are-required-for-core-histone-gene-transcription
#10
Yuko Takayama, Masaki Shirai, Fumie Masuda
Histone gene expression is regulated in a cell cycle-dependent manner, with a peak at S phase, which is crucial for cell division and genome integrity. However, the detailed mechanisms by which expression of histone genes are tightly regulated remain largely unknown. Fission yeast Ams2, a GATA-type zinc finger motif-containing factor, is required for activation of S phase-specific core histone gene transcription. Here we report the molecular characterisation of Ams2. We show that the zinc finger motif in Ams2 is necessary to bind the histone gene promoter region and to activate histone gene transcription...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27898391/replication-fork-instability-and-the-consequences-of-fork-collisions-from-rereplication
#11
REVIEW
Jessica L Alexander, Terry L Orr-Weaver
Replication forks encounter obstacles that must be repaired or bypassed to complete chromosome duplication before cell division. Proteomic analysis of replication forks suggests that the checkpoint and repair machinery travels with unperturbed forks, implying that they are poised to respond to stalling and collapse. However, impaired fork progression still generates aberrations, including repeat copy number instability and chromosome rearrangements. Deregulated origin firing also causes fork instability if a newer fork collides with an older one, generating double-strand breaks (DSBs) and partially rereplicated DNA...
October 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27883035/telomeres-are-elongated-in-older-individuals-in-a-hibernating-rodent-the-edible-dormouse-glis-glis
#12
Franz Hoelzl, Steve Smith, Jessica S Cornils, Denise Aydinonat, Claudia Bieber, Thomas Ruf
Telomere shortening is thought to be an important biomarker for life history traits such as lifespan and aging, and can be indicative of genome integrity, survival probability and the risk of cancer development. In humans and other animals, telomeres almost always shorten with age, with more rapid telomere attrition in short-lived species. Here, we show that in the edible dormouse (Glis glis) telomere length significantly increases from an age of 6 to an age of 9 years. While this finding could be due to higher survival of individuals with longer telomeres, we also found, using longitudinal measurements, a positive effect of age on the rate of telomere elongation within older individuals...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27881872/in-vitro-and-in-vivo-assessment-of-direct-effects-of-simulated-solar-and-galactic-cosmic-radiation-on-human-hematopoietic-stem-progenitor-cells
#13
C Rodman, G Almeida-Porada, S K George, J Moon, S Soker, T Pardee, M Beaty, P Guida, S P Sajuthi, C D Langefeld, S J Walker, P F Wilson, C D Porada
Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL...
December 9, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27879221/generation-of-a-tle3-heterozygous-knockout-human-embryonic-stem-cell-line-using-crispr-cas9
#14
Anne M Bara, Angelica Messana, Amanda Herring, Dane Z Hazelbaker, Kevin Eggan, Lindy E Barrett
Here, we generated a monoallelic mutation in the TLE3 (Transducin Like Enhancer of Split 3) gene using CRISPR-Cas9 editing in the human embryonic stem cell (hESC) line WA01. The heterozygous knockout cell line, TLE3-447-D08-A01, displays partial loss of TLE3 protein expression while maintaining pluripotency, differentiation potential and genomic integrity.
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27879218/generation-of-a-tle1-homozygous-knockout-human-embryonic-stem-cell-line-using-crispr-cas9
#15
Amanda Herring, Angelica Messana, Anne M Bara, Dane Z Hazelbaker, Kevin Eggan, Lindy E Barrett
Here, we generated a biallelic mutation in the TLE1 (Transducin Like Enhancer of Split 1) gene using CRISPR-Cas9 editing in the human embryonic stem cell (hESC) line WA01. The homozygous knockout cell line, TLE1-464-G04, displays loss of TLE1 protein expression while maintaining pluripotency, differentiation potential and genomic integrity.
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27879207/integration-free-erythroblast-derived-human-induced-pluripotent-stem-cells-ipscs-from-an-individual-with-ataxia-telangiectasia-a-t
#16
Niraj Bhatt, Rajib Ghosh, Sanchita Roy, Yongxing Gao, Mary Armanios, Linzhao Cheng, Sonia Franco
Peripheral blood was obtained from a 12-year old male carrying bialleleic inactivating mutations at the ATM locus, causing Ataxia-Telangiectasia (A-T). Blood erythroid cells were briefly expanded in vitro and induced pluripotent stem cells (iPSCs) were generated via transfection with episomal vectors carrying hOCT4, hSOX2, hKLF4, hMYC and hBCL2L1. SF-003 iPSCs were free of genomically integrated reprogramming genes, had the specific compound heterozygous mutations, stable karyotype, expressed pluripotency markers and formed teratomas in immunodeficient (NOD scid gamma; NGS) mice...
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27878651/messages-on-small-rna-duplexes-in-plants
#17
Taichiro Iki
Small RNA-mediated gene silencing encompasses diverse developmental events, stress responses, defense against pathogens, and maintenance of genome integrity. Extensive studies in model organisms have unveiled the molecular mechanisms underpinning the RNA silencing phenomena, and the accumulating knowledge have characterized the intricate pathways and the repertoire of proteins responsible for the actions of small RNAs characterized as microRNAs (miRNAs) or small interfering RNAs (siRNAs). Although the single-stranded, matured guide small RNAs direct the effector ribonucleoprotein complexes to induce gene silencing in sequence-specific manner, the double-stranded intermediate, the small RNA duplexes, which are processed as nascent products of the RNase III enzyme activities, act as key to determine the downstream molecular pathways and the fate of small RNAs...
November 23, 2016: Journal of Plant Research
https://www.readbyqxmd.com/read/27878300/induction-of-dna-damage-and-apoptosis-in-human-leukemia-cells-by-efavirenz
#18
Ansgar Brüning, Julia Jückstock, Bernd Kost, Panagiotis Tsikouras, Tobias Weissenbacher, Sven Mahner, Ioannis Mylonas
As part of the efforts to drug repurposing, some HIV drugs have recently been identified to exert anticancer effects. Selected nucleoside analogues of nucleosidic reverse-transcriptase inhibitors (NRTIs) have been shown to interfere with RNA transcription of HI viruses as well as with the replication of DNA in cancer cells. Non-nucleosidic reverse transcriptase inhibitors (NNRTIs) are believed to have less effects on human DNA replication and, thus, on cancer cell proliferation. Assessment of the effect of the NNRTI efavirenz in human cancer cells, however, revealed a high sensitivity of leukemia cells to this agent at pharmacologically relevant concentrations of less than 10 µg/ml...
November 15, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27878232/involvement-of-bleomycin-hydrolase-and-poly-adp-ribose-polymerase-1-in-ubc9-mediated-resistance-to-chemotherapy-agents
#19
Yang Chen, Huixian Zhang, Qiyang He
Ubiquitin-conjugating protein 9 (Ubc9), the sole enzyme for sumoylation, plays critical roles in many physiological functions, such as DNA damage repair and genome integrity. Its overexpression led to poor prognosis and drug resistance in tumor chemotherapy. However, the underlying mechanism by which Ubc9 promotes tumor progress and influences the susceptibility to antitumor agents remains elusive. In this study, we used nine antitumor agents with distinct actions to explore Ubc9-mediated resistance in human breast carcinoma MCF-7 cells...
November 23, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27876123/blm-germline-and-somatic-pkmyt1-and-ahcy-mutations-genetic-variations-beyond-mycn-and-prognosis-in-neuroblastoma
#20
E M Novak, N S Halley, T M Gimenez, A Rangel-Santos, A M P Azambuja, M Brumatti, P L Pereira, C S C Vince, R R Giorgi, I Bendit, L M Cristofani, V Odone-Filho
Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood and often lethal in childhood. Clinical and biologic characteristics that are independently prognostic of outcome in NB are currently used for risk stratification to optimally the therapy. It includes age at diagnosis, International Neuroblastoma Staging System tumor histopathology and MYCN amplification. However, even in patients with theoretically good prognosis, such as localized tumor and non-amplified MYCN, either disease progress or recurrence may occur...
December 2016: Medical Hypotheses
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