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https://www.readbyqxmd.com/read/29142505/targeting-deubiquitinating-enzymes-in-cancer-stem-cells
#1
REVIEW
Hu Lei, Huizhuang Shan, Yingli Wu
Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#2
Jonathan D Wrigley, Gerald Gavory, Iain Simpson, Marian Preston, Helen Plant, Jenna Bradley, Anne U Goeppert, Ewelina Rozycka, Gareth Davies, Jarrod Walsh, Andrea Valentine, Keeva McClelland, Krzysztofa Ewa Odrzywol, Jonathan Renshaw, Joanna Boros, Jonathan Tart, Lindsey Leach, Thorsten Nowak, Richard A Ward, Timothy Harrison, David M Andrews
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29126920/the-fentanyl-epidemic-in-canada-some-cautionary-observations-focusing-on-opioid-related-mortality
#3
Benedikt Fischer, Lenka Vojtila, Jürgen Rehm
In Canada, opioid-related overdose mortality has steeply increased in recent years; as a substantial number of opioid-related deaths are related to 'fentanyl' products, this phenomenon has widely been dubbed the 'fentanyl epidemic', also implying that these deaths are largely caused by clandestinely 'illicit fentanyl' products. We examined numbers and rates of opioid- and fentanyl-related deaths in six pan-Canadian provinces with respective (coroner-based) data available from 2010 to 2016. While fentanyl-related deaths are clearly increasing from relatively low levels in all provinces, those increases are strongest in the two Western provinces (e...
November 7, 2017: Preventive Medicine
https://www.readbyqxmd.com/read/29126218/libra-wa-a-web-application-for-ligand-binding-site-detection-and-protein-function-recognition
#4
Daniele Toti, Viet Hung Le, Valentina Tortosa, Valentina Brandi, Fabio Polticelli
Summary: Recently, LIBRA, a tool for active/ligand binding site prediction, was described. LIBRA's effectiveness was comparable to similar state-of-the-art tools; however, its scoring scheme, output presentation, dependence on local resources and overall convenience were amenable to improvements. To solve these issues, LIBRA-WA, a web application based on an improved LIBRA engine, has been developed, featuring a novel scoring scheme consistently improving LIBRA's performance, and a refined algorithm that can identify binding sites hosted at the interface between different subunits...
November 6, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29117247/a-mobile-loop-near-the-active-site-acts-as-a-switch-between-the-dual-activities-of-a-viral-protease-deubiquitinase
#5
Isabelle Jupin, Maya Ayach, Lucile Jomat, Sonia Fieulaine, Stéphane Bressanelli
The positive-strand RNA virus Turnip yellow mosaic virus (TYMV) encodes an ovarian tumor (OTU)-like protease/deubiquitinase (PRO/DUB) protein domain involved both in proteolytic processing of the viral polyprotein through its PRO activity, and in removal of ubiquitin chains from ubiquitylated substrates through its DUB activity. Here, the crystal structures of TYMV PRO/DUB mutants and molecular dynamics simulations reveal that an idiosyncratic mobile loop participates in reversibly constricting its unusual catalytic site by adopting "open", "intermediate" or "closed" conformations...
November 8, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29111377/mass-spectrometry-analyses-of-normal-and-polyglutamine-expanded-ataxin-3-reveal-novel-interaction-partners-involved-in-mitochondrial-function
#6
Line V Kristensen, Felix S Oppermann, Matthias J Rauen, Karina Fog, Thorsten Schmidt, Jana Schmidt, Tina Harmuth, Rasmus Hartmann-Petersen, Kenneth Thirstrup
Deubiquitinating enzymes (DUBs) play important roles in a variety of cellular processes, including regulation of protein homeostasis. The DUB ataxin-3 is an enzyme implicated in protein quality control mechanisms. In the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3), ataxin-3 contains an expanded polyglutamine (polyQ) stretch that leads to aggregation of the protein and neuronal dysfunction. Increasing the understanding of ataxin-3 protein interaction partners could help to elucidate disease mechanisms...
October 27, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29111344/the-crystal-structure-and-conformations-of-an-unbranched-mixed-tri-ubiquitin-chain-containing-k48-and-k63-linkages
#7
Prasanth Padala, Nadine Soudah, Moshe Giladi, Yoni Haitin, Michail N Isupov, Reuven Wiener
The ability of ubiquitin to function in a wide range of cellular processes is ascribed to its capacity to cause a diverse spectrum of modifications. While a target protein can be modified with monoubiquitin, it can also be modified with ubiquitin chains. The latter include seven types of homotypic chains as well as mixed ubiquitin chains. In a mixed chain, not all the isopeptide bonds are restricted to a specific lysine of ubiquitin, resulting in a chain possessing more than one type of linkage. While structural characterization of homotypic chains has been well elucidated, less is known about mixed chains...
October 27, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29106644/iuucd-2-0-an-update-with-rich-annotations-for-ubiquitin-and-ubiquitin-like-conjugations
#8
Jiaqi Zhou, Yang Xu, Shaofeng Lin, Yaping Guo, Wankun Deng, Ying Zhang, Anyuan Guo, Yu Xue
Here, we described the updated database iUUCD 2.0 (http://iuucd.biocuckoo.org/) for ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin-protein ligases (E3s), deubiquitinating enzymes (DUBs), ubiquitin/ubiquitin-like binding domains (UBDs) and ubiquitin-like domains (ULDs), which act as key regulators in modulating ubiquitin and ubiquitin-like (UB/UBL) conjugations. In total, iUUCD 2.0 contained 136 512 UB/UBL regulators, including 1230 E1s, 5636 E2s, 93 343 E3s, 9548 DUBs, 30 173 UBDs and 11 099 ULDs in 148 eukaryotic species...
November 2, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29101536/vib-bracelet-a-passive-absorber-for-attenuating-forearm-tremor
#9
Eran Buki, Reuven Katz, Miriam Zacksenhouse, Ilana Schlesinger
Tremor is a rhythmic, involuntary, oscillatory movement of a limb produced by alternating contractions of reciprocally innervated muscles. More than 4% of the population over 40 years old suffer from tremor. There is no cure for most tremors, and while psychological therapy is sometimes helpful, tremors are usually treated with either medication or invasive surgery including thalamotomy and deep brain stimulation. Both medications and surgery may have adverse effects, and thus, there is a growing interest in developing non-invasive vibration attenuation devices...
November 4, 2017: Medical & Biological Engineering & Computing
https://www.readbyqxmd.com/read/29101126/induction-of-deubiquitinating-enzyme-usp50-during-erythropoiesis-and-its-potential-role-in-the-regulation-of-ku70-stability
#10
Junting Cai, Jianxin Wei, Valerie Schrott, Jing Zhao, Grant Bullock, Yutong Zhao
Anemia is a very common blood disorder that affects the lives of billions of people worldwide. Anemia is caused by the loss of blood, increased destruction of red blood cells (RBCs), or reduced production of RBCs. Erythropoiesis is the complex process of RBC differentiation and maturation, in which protein degradation plays a crucial role. Protein ubiquitination regulates programmed protein degradation, which can be reversed by deubiquitinating enzymes (DUBs); however, the role of DUBs in erythropoiesis has not been well studied...
November 3, 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
https://www.readbyqxmd.com/read/29098502/cadmium-pyrithione-suppresses-tumor-growth-in-vitro-and-in-vivo-through-inhibition-of-proteasomal-deubiquitinase
#11
Xin Chen, Jinjie Wu, Qianqian Yang, Xiaolan Zhang, Peiquan Zhang, Siyan Liao, Zhimin He, Xuejun Wang, Chong Zhao, Jinbao Liu
The ubiquitin-proteasome system (UPS) is indispensable to the protein quality control in eukaryotic cells. Due to the remarkable clinical success of using proteasome inhibitors for clinical treatment of multiple myeloma, it is anticipated that targeting the UPS upstream of the proteasome step be an effective strategy for cancer therapy. Deubiquitinases (DUB) are proteases that remove ubiquitin from target proteins and therefore regulate multiple cellular processes including some signaling pathways altered in cancer cells...
November 3, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/29091922/characterization-of-the-deubiquitination-activity-and-substrate-specificity-of-the-chicken-ubiquitin-specific-protease-1-usp-associated-factor-1-complex
#12
Hainan Zheng, Mengyun Wang, Chengcheng Zhao, Shanli Wu, Peifeng Yu, Yan Lü, Tiedong Wang, Yongxing Ai
Deubiquitinases (DUBs) are essential regulators of intracellular processes involving ubiquitin (Ub) modification. The human DUB ubiquitin-specific protease 1 (hUSP1) interacts with human USP-associated factor 1 (hUAF1), and helps to regulate processes such as DNA damage repair. Previously, we identified a chicken USP1 homologue (chUSP1) during an investigation into the properties of Marek's disease virus (MDV). However, chUSP1's deubiquitination activity, interaction with chUAF1, and substrate specificity remained unknown...
2017: PloS One
https://www.readbyqxmd.com/read/29082289/method-for-multiplexing-crispr-cas9-in-saccharomyces-cerevisiae-using-artificial-target-dna-sequences
#13
Rachael M Giersch, Gregory C Finnigan
Genome manipulation has become more accessible given the advent of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) editing technology. The Cas9 endonuclease binds a single stranded (single guide) RNA (sgRNA) fragment that recruits the complex to a corresponding genomic target sequence where it induces a double stranded break. Eukaryotic repair systems allow for the introduction of exogenous DNA, repair of existing mutations, or deletion of endogenous gene products. Targeting of Cas9 to multiple genomic positions (termed 'multiplexing') is achieved by the expression of multiple sgRNAs within the same nucleus...
September 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29082104/dramatic-enhancement-of-the-detection-limits-of-bioassays-via-ultrafast-deposition-of-polydopamine
#14
Junwei Li, Madison A Baird, Michael A Davis, Wanyi Tai, Larry S Zweifel, Kristina M Adams Waldorf, Michael Gale, Lakshmi Rajagopal, Robert H Pierce, Xiaohu Gao
The ability to detect biomarkers with ultrahigh sensitivity radically transformed biology and disease diagnosis. However, owing to incompatibilities with infrastructure in current biological and medical laboratories, recent innovations in analytical technology have not received broad adoption. Here, we report a simple, universal 'add-on' technology (dubbed EASE) that can be directly plugged into the routine practices of current research and clinical laboratories and that converts the ordinary sensitivities of common bioassays to extraordinary ones...
2017: Nature biomedical engineering
https://www.readbyqxmd.com/read/29080080/ubiquitin-carboxyl-terminal-hydrolases-involvement-in-cancer-progression-and-clinical-implications
#15
Ying Fang, Xizhong Shen
Protein ubiquitination and deubiquitination participate in a number of biological processes, including cell growth, differentiation, transcriptional regulation, and oncogenesis. Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), includes four members: UCH-L1/PGP9.5 (protein gene product 9.5), UCH-L3, UCHL5/UCH37, and BRCA1-associated protein-1 (BAP1). Recently, more attention has been paid to the relationship between the UCH family and malignancies, which play different roles in the progression of different tumors...
October 27, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29079801/development-of-a-curative-therapeutic-vaccine-theravac-for-the-treatment-of-large-established-tumors
#16
Yingjie Nie, De Yang, Anna Trivett, Zhen Han, Haiyun Xin, Xin Chen, Joost J Oppenheim
Harnessing immune system to treat cancer requires simultaneous generation of tumor-specific CTLs and curtailment of tumor immunosuppressive environment. Here, we developed an immunotherapeutic regimen capable of eliminating large established mouse tumors using HMGN1, a DC-activating TLR4 agonist capable of inducing anti-tumor immunity. Intratumoral delivery of HMGN1 with low dose of Cytoxan cured mice bearing small (∅ ≈ 0.5 cm), but not large (∅ ≈ 1.0 cm) CT26 tumors. Screening for activators capable of synergizing with HMGN1 in activating DC identified R848...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29079682/arsda-a-new-approach-for-storing-transmitting-and-analyzing-transcriptomic-data
#17
Xuhua Xia
Two major stumbling blocks exist in high-throughput sequencing (HTS) data analysis. The first is the sheer file size typically in gigabytes when uncompressed, causing problems in storage, transmission and analysis. However, these files do not need to be so large and can be reduced without loss of information. Each HTS file, either in compressed .SRA or plain text .fastq format, contains numerous identical reads stored as separate entries. For example, among 44603541 forward reads in the SRR4011234.sra file (from a Bacillus subtilis transcriptomic study) deposited at NCBI's SRA database, one read has 497027 identical copies...
October 27, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29078313/ultraaccurate-genome-sequencing-and-haplotyping-of-single-human-cells
#18
Wai Keung Chu, Peter Edge, Ho Suk Lee, Vikas Bansal, Vineet Bafna, Xiaohua Huang, Kun Zhang
Accurate detection of variants and long-range haplotypes in genomes of single human cells remains very challenging. Common approaches require extensive in vitro amplification of genomes of individual cells using DNA polymerases and high-throughput short-read DNA sequencing. These approaches have two notable drawbacks. First, polymerase replication errors could generate tens of thousands of false-positive calls per genome. Second, relatively short sequence reads contain little to no haplotype information. Here we report a method, which is dubbed SISSOR (single-stranded sequencing using microfluidic reactors), for accurate single-cell genome sequencing and haplotyping...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29074263/novel-subfamilies-of-actin-regulating-proteins
#19
A A Morozov, Ye D Bedoshvili, M S Popova, Ye V Likhoshway
Ability of actin to polymerise and depolymerise makes it essential to key functions of eukaryotic cell. The functioning of actin is controlled by a host of regulatory proteins, the repertoire of which in diatoms is known to remarkably differ from other organisms. We have performed a phylogenetic analysis of 521 actin and actin-related proteins' aminoacid sequences, as well as 190 sequences of gelsolin family proteins from various genomic and transcriptomic datasets. Based on the results of this analysis, as well as on the presence of clade-specific indels in some of the actin-related proteins, we describe a novel ARP subfamily, dubbed ARP12, which is specific to heterokonts and related organisms...
October 23, 2017: Marine Genomics
https://www.readbyqxmd.com/read/29069806/modulating-bap1-expression-affects-ros-homeostasis-cell-motility-and-mitochondrial-function
#20
Lucie Hebert, Dorine Bellanger, Chloé Guillas, Antoine Campagne, Florent Dingli, Damarys Loew, Alice Fievet, Virginie Jacquemin, Tatiana Popova, Didier Jean, Fatima Mechta-Grigoriou, Raphaël Margueron, Marc-Henri Stern
The tumor suppressor BAP1 associates with ASXL1/2 to form the core Polycomb complex PR-DUB, which catalyzes the removal of mono-ubiquitin from several substrates including histone H2A. This complex also mediates the poly-deubiquitination of HCFC1, OGT and PCG1-α, preventing them from proteasomal degradation. Surprisingly, considering its role in a Polycomb complex, no transcriptional signature was consistently found among BAP1-inactivated tumor types. It was hypothesized that BAP1 tumor suppressor activity could reside, at least in part, in stabilizing proteins through its poly-deubiquitinase activity...
September 22, 2017: Oncotarget
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