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JOURNAL ARTICLE
Zijing Chen, Jing Hu, Jingli Dai, Congli Zhou, Yuejin Hua, Xiaoting Hua, Ye Zhao
Deinococcus radiodurans, with its high homologous recombination (HR) efficiency of double-stranded DNA breaks (DSBs), is a model organism for studying genome stability maintenance and an attractive microbe for industrial applications. Here, we developed an efficient CRISPR/Cpf1 genome editing system in D. radiodurans by evaluating and optimizing double-plasmid strategies and four Cas effector proteins from various organisms, which can precisely introduce different types of template-dependent mutagenesis without off-target toxicity...
April 9, 2024: Microbiological Research
#22
REVIEW
Sachi Khemka, Ujala Sehar, Pulak R Manna, Sudhir Kshirsagar, P Hemachandra Reddy
Alzheimer's disease (AD) and Alzheimer's disease-related disorders (ADRD) are progressive neurodegenerative diseases without cure. Alzheimer's disease occurs in 2 forms, early-onset familial AD and late-onset sporadic AD. Early-onset AD is a rare (~1%), autosomal dominant, caused by mutations in presenilin-1, presenilin-2, and amyloid precursor protein genes and the other is a late-onset, prevalent and is evolved due to age-associated complex interactions between environmental and genetic factors, in addition to apolipoprotein E4 polymorphism...
April 4, 2024: Aging and Disease
#23
JOURNAL ARTICLE
Alexandria A Oviatt, Elizabeth G Gibson, Jianzhong Huang, Karen Mattern, Keir C Neuman, Pan F Chan, Neil Osheroff
Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including Escherichia coli , were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from E...
April 12, 2024: ACS Infectious Diseases
#24
JOURNAL ARTICLE
Thomas Balan, Leticia Koch Lerner, Daniel Holoch, Sandra Duharcourt
Transposable elements and other repeats are repressed by small-RNA-guided histone modifications in fungi, plants and animals. The specificity of silencing is achieved through base-pairing of small RNAs corresponding to the these genomic loci to nascent noncoding RNAs, which allows the recruitment of histone methyltransferases that methylate histone H3 on lysine 9. Self-reinforcing feedback loops enhance small RNA production and ensure robust and heritable repression. In the unicellular ciliate Paramecium tetraurelia, small-RNA-guided histone modifications lead to the elimination of transposable elements and their remnants, a definitive form of repression...
2024: Wiley Interdisciplinary Reviews. RNA
#25
JOURNAL ARTICLE
Baoqiang Fu, Tao Chen, Bin Jiang, Haobin Feng, Ziyu Zhu, Min Li, Guoxing Zhang, Yan Jiang
Recently, attention has been drawn to the adverse outcomes of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ) on human health, but its cardiac toxicity has been relatively understudied. This work aims to investigate the effects of 6PPDQ on differentiated H9c2 cardiomyocytes. Our findings demonstrated that exposure to 6PPDQ altered cellular morphology and disrupted the expression of cardiac-specific markers. Significantly, 6PPDQ exposure led to cardiomyocyte senescence, characterized by elevated β-Galactosidase activity, upregulation of cell cycle inhibitor, induction of DNA double-strand breaks, and remodeling of Lamin B1...
April 9, 2024: Environmental Pollution
#26
JOURNAL ARTICLE
Marlène Vayssières, Nils Marechal, Long Yun, Brian Lopez Duran, Naveen Kumar Murugasamy, Jonathan M Fogg, Lynn Zechiedrich, Marc Nadal, Valérie Lamour
DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules, enabling the transport of one duplex through the transient double-stranded break of the other, remains elusive owing to structures derived solely from single linear duplex DNAs lacking topological constraints. Using cryo-electron microscopy, we solved the structure of Escherichia coli DNA gyrase bound to a negatively supercoiled minicircle DNA. We show how DNA gyrase captures a DNA crossover, revealing both conserved molecular grooves that accommodate the DNA helices...
April 12, 2024: Science
#27
JOURNAL ARTICLE
Nada Kojak, Junko Kuno, Kristina E Fittipaldi, Ambereen Khan, David Wenger, Michael Glasser, Roberto A Donnianni, Yajun Tang, Jade Zhang, Katie Huling, Roxanne Ally, Alejandro O Mujica, Terrence Turner, Gina Magardino, Pei Yi Huang, Sze Yen Kerk, Gustavo Droguett, Marine Prissette, Jose Rojas, Teodoro Gomez, Anthony Gagliardi, Charleen Hunt, Jeremy S Rabinowitz, Guochun Gong, William Poueymirou, Eric Chiao, Brian Zambrowicz, Chia-Jen Siao, Daisuke Kajimura
Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate the underlying mechanisms of repeat instability, which occurs both somatically and intergenerationally, we created a novel mouse model of familial ALS/FTD that harbors 96 copies of G4C2 repeats at a humanized C9orf72 locus. In mouse embryonic stem cells, we observed two modes of repeat expansion. First, we noted minor increases in repeat length per expansion event, which was dependent on a mismatch repair pathway protein Msh2...
April 10, 2024: Nucleic Acids Research
#28
JOURNAL ARTICLE
Kenichiro Matsuzaki, Akira Shinohara, Miki Shinohara
RAD51 filament is crucial for the homology-dependent repair of DNA double-strand breaks and stalled DNA replication fork protection. Positive and negative regulators control RAD51 filament assembly and disassembly. RAD51 is vital for genome integrity but excessive accumulation of RAD51 on chromatin causes genome instability and growth defects. However, the detailed mechanism underlying RAD51 disassembly by negative regulators and the physiological consequence of abnormal RAD51 persistence remain largely unknown...
April 10, 2024: Nucleic Acids Research
#29
REVIEW
Maiko Kitaoka, Yukiko M Yamashita
Species' continuity depends on gametogenesis to produce the only cell types that can transmit genetic information across generations. Spermiogenesis, which encompasses post-meiotic, haploid stages of male gametogenesis, is a process that leads to the formation of sperm cells well-known for their motility. Spermiogenesis faces three major challenges. First, after two rounds of meiotic divisions, the genome lacks repair templates (no sister chromatids, no homologous chromosomes), making it incredibly vulnerable to any genomic insults over an extended time (typically days-weeks)...
December 2024: Nucleus
#30
JOURNAL ARTICLE
Yi-Tzu Kuo, Veit Schubert, André Marques, Ingo Schubert, Andreas Houben
In addition to monocentric eukaryotes, which have a single localized centromere on each chromosome, there are holocentric species, with extended repeat-based or repeat-less centromeres distributed over the entire chromosome length. At least two types of repeat-based holocentromeres exist, one composed of many small repeat-based centromere units (small unit-type), and another one characterized by a few large centromere units (large unit-type). We hypothesize that the transposable element-mediated dispersal of hundreds of short satellite arrays formed the small centromere unit-type holocentromere in Rhynchospora pubera...
April 9, 2024: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
#31
JOURNAL ARTICLE
Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda
Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death...
April 9, 2024: Science Signaling
#32
JOURNAL ARTICLE
Francisco Navas, Ana Chocarro-Calvo, Patricia Iglesias-Hernández, Paloma Fernández-García, Victoria Morales, José Manuel García-Martínez, Raúl Sanz, Antonio De la Vieja, Custodia García-Jiménez, Rafael A García-Muñoz
We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis -dichloro(diamine)- trans -[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis -dichloro(diisopropylamine)- trans -[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6)...
April 9, 2024: Journal of Medicinal Chemistry
#33
Amit Singh, Sabyasachi Senapati, Inusha Panigrahi, Preeti Khetarpal
BACKGROUND: LIG4 syndrome, characterized by immunodeficiency, sensitivity to ionizing radiations, intrauterine growth retardation, postnatal growth retardation, and microcephaly, is a rare genetic disorder caused by pathogenic variants of the LIG4 gene. Few patients are presented with no immune dysregulation as well. CASE STUDY: We present here a male child of 2 years and 4 months of age with severe microcephaly and short stature. His birth weight was 1.9 Kg, and his current height, weight, and head circumference are 83...
April 8, 2024: Current Pediatric Reviews
#34
JOURNAL ARTICLE
Tokiwa Motonari, Yuki Yoshino, Moe Haruta, Shino Endo, Shota Sasaki, Minoru Miyashita, Hiroshi Tada, Gou Watanabe, Toshiro Kaneko, Takanori Ishida, Natsuko Chiba
Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents...
April 8, 2024: Scientific Reports
#35
JOURNAL ARTICLE
Oran McElligott, Mihails Nikandrovs, Patrick McCavana, Brendan McClean, Luis León Vintró
BACKGROUND: The Relative Biological Effectiveness (RBE) of kilovoltage photon beams has been previously investigated in vitro and in silico using analytical methods. The estimated values range from 1.03 to 1.82 depending on the methodology and beam energies examined. PURPOSE: The focus of this work was to independently estimate RBE values for a range of clinically used kilovoltage beams (70-200 kVp) while investigating the suitability of using TOPAS-nBio for this task...
April 8, 2024: Medical Physics
#36
JOURNAL ARTICLE
Shilpa Padmanaban, Nils J Lambacher, Valerie M Tesmer, Jingjing Zhang, Hiroki Shibuya, Jayakrishnan Nandakumar
Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited...
April 16, 2024: Proceedings of the National Academy of Sciences of the United States of America
#37
JOURNAL ARTICLE
Gabriele Picco, Yanhua Rao, Angham Al Saedi, Yang Lee, Sara F Vieira, Shriram Bhosle, Kieron May, Carmen Herranz-Ors, Samantha J Walker, Raynold Shenje, Cansu Dincer, Freddy Gibson, Ruby Banerjee, Zoe Hewitson, Thilo Werner, Joshua E Cottom, Yang Peng, Nanhua Deng, Philip Landis, Daniela Conticelli, Katrina McCarten, Jacob Bush, Mamta Sharma, Howard Lightfoot, David House, Emma Milford, Emma K Grant, Michal P Glogowski, Craig D Wagner, Marcus Bantscheff, Anna Rutkowska-Klute, Cell Model Network Uk Group, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, H Christian Eberl, Brian T Jones, Jessica L Schneck, Dennis J Murphy, Emile E Voest, Joshua P Taygerly, Michael P DeMartino, Matthew A Coelho, Jonathan Houseley, Geeta Sharma, Benjamin J Schwartz, Mathew J Garnett
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage...
April 9, 2024: Cancer Discovery
#38
JOURNAL ARTICLE
Ali Bakr, Giuditta Della Corte, Olivera Veselinov, Simge Kelekçi, Mei-Ju May Chen, Yu-Yu Lin, Gianluca Sigismondo, Marika Iacovone, Alice Cross, Rabail Syed, Yunhee Jeong, Etienne Sollier, Chun-Shan Liu, Pavlo Lutsik, Jeroen Krijgsveld, Dieter Weichenhan, Christoph Plass, Odilia Popanda, Peter Schmezer
AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII...
April 8, 2024: Nucleic Acids Research
#39
Surajit Chatterjee, Loïc Chaubet, Aafke van den Berg, Ann Mukhortava, Mitch Gulkis, Melike Çağlayan
DNA ligases repair the strand breaks are made continually and naturally throughout the genome, if left unrepaired and allowed to persist, they can lead to genome instability in the forms of lethal double-strand (ds) breaks, deletions, and duplications. DNA ligase 1 (LIG1) joins Okazaki fragments during the replication machinery and seals nicks at the end of most DNA repair pathways. Yet, how LIG1 recognizes its target substrate is entirely missing. Here, we uncover the dynamics of nick DNA binding by LIG1 at the single-molecule level...
March 29, 2024: bioRxiv
#40
Cicera R Lazzarotto, Varun Katta, Yichao Li, Elizabeth Urbina, GaHyun Lee, Shengdar Q Tsai
Base editors ( BE ) enable programmable conversion of nucleotides in genomic DNA without double-stranded breaks and have substantial promise to become new transformative genome editing medicines. Sensitive and unbiased detection of base editor off-target effects is important for identifying safety risks unique to base editors and translation to human therapeutics, as well as accurate use in life sciences research. However, current methods for understanding the global activities of base editors have limitations in terms of sensitivity or bias...
March 30, 2024: bioRxiv
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