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  • 1
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    Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion (2013)
    Oxford University Press
    Details
    Publication Date: 2013-09-26
    Description: The p53 core domain binds to response elements (REs) that contain two continuous half-sites as a cooperative tetramer, but how p53 recognizes discontinuous REs is not well understood. Here we describe the crystal structure of the p53 core domain bound to a naturally occurring RE located at the promoter of the Bcl-2-associated X protein (BAX) gene, which contains a one base-pair insertion between the two half-sites. Surprisingly, p53 forms a tetramer on the BAX-RE that is nearly identical to what has been reported on other REs with a 0-bp spacer. Each p53 dimer of the tetramer binds in register to a half-site and maintains the same protein–DNA interactions as previously observed, and the two dimers retain all the protein–protein contacts without undergoing rotation or translation. To accommodate the additional base pair, the DNA is deformed and partially disordered around the spacer region, resulting in an apparent unwinding and compression, such that the interactions between the dimers are maintained. Furthermore, DNA deformation within the p53-bound BAX-RE is confirmed in solution by site-directed spin labeling measurements. Our results provide a structural insight into the mechanism by which p53 binds to discontinuous sites with one base-pair spacer.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Nearly ferromagnetic spin-triplet superconductivity (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉Spin-triplet superconductors potentially host topological excitations that are of interest for quantum information processing. We report the discovery of spin-triplet superconductivity in UTe〈sub〉2〈/sub〉, featuring a transition temperature of 1.6 kelvin and a very large and anisotropic upper critical field exceeding 40 teslas. This superconducting phase stability suggests that UTe〈sub〉2〈/sub〉 is related to ferromagnetic superconductors such as UGe〈sub〉2〈/sub〉, URhGe, and UCoGe. However, the lack of magnetic order and the observation of quantum critical scaling place UTe〈sub〉2〈/sub〉 at the paramagnetic end of this ferromagnetic superconductor series. A large intrinsic zero-temperature reservoir of ungapped fermions indicates a highly unconventional type of superconducting pairing.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Structural insights into the EGO-TC-mediated membrane tethering of the TORC1-regulatory Rag GTPases (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉The Rag/Gtr GTPases serve as a central module in the nutrient-sensing signaling network upstream of TORC1. In yeast, the anchoring of Gtr1-Gtr2 to membranes depends on the Ego1-Ego2-Ego3 ternary complex (EGO-TC), resulting in an EGO-TC-Gtr1-Gtr2 complex (EGOC). EGO-TC and human Ragulator share no obvious sequence similarities and also differ in their composition with respect to the number of known subunits, which raises the question of how the EGO-TC fulfills its function in recruiting Gtr1-Gtr2. Here, we report the structure of EGOC, in which Ego1 wraps around Ego2, Ego3, and Gtr1-Gtr2. In addition, Ego3 interacts with Gtr1-Gtr2 to stabilize the complex. The functional roles of key residues involved in the assembly are validated by in vivo assays. Our structural and functional data combined demonstrate that EGOC and Ragulator-Rag complex are structurally conserved and that EGO-TC is essential and sufficient to recruit Gtr1-Gtr2 to membranes to ensure appropriate TORC1 signaling.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    RNAe: an effective method for targeted protein translation enhancement by artificial non-coding RNA with SINEB2 repeat (2015)
    Oxford University Press
    Details
    Publication Date: 2015-05-20
    Description: In this study, a universal protein expression enhancement RNA tool, termed RNAe, was developed by modifying a recently discovered natural long non-coding RNA. At the moment, RNAe is the only technology for gene expression enhancement, as opposed to silencing, at the post-transcriptional level. With this technology, an expression enhancement of 50–1000% is achievable, with more than 200% enhancement achieved in most cases. This work identified the sufficient and necessary element for RNAe function, which was found to be merely 300 nucleotides long and was named minRNAe. It contains a 72-nt 5' pairing sequence which determines the specificity, a 167-nt short non-pairing interspersed nuclear element (SINE) B2 sequence which enhances ribosome recruitment to the target mRNA, and a poly(A) tail, provided together on a plasmid bearing the appropriate sequences. Cellular delivery of RNAe was achieved using routine transfection. The RNAe platform was validated in several widely-used mammalian cell lines. It was proven to be efficient and flexible in specifically enhancing the expression of various endogenous and exogenous proteins of diverse functions in a dose-dependent manner. Compared to the expression-inhibitory tool RNAi, the RNAe tool has a comparable effect size, with an enhancing as opposed to inhibitory effect. One may predict that this brand new technology for enhancing the production of proteins will find wide applications in both research and biopharmaceutical production.
    Keywords: Recombinant DNA expression, Ribosomes and Protein Translation
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Oxygen isotopes of East Asian dinosaurs reveal exceptionally cold Early Cretaceous climates [Geology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-03-30
    Description: Early Cretaceous vertebrate assemblages from East Asia and particularly the Jehol Biota of northeastern China flourished during a period of highly debated climatic history. While the unique characters of these continental faunas have been the subject of various speculations about their biogeographic history, little attention has been paid to their possible climatic causes. Here we address this question using the oxygen isotope composition of apatite phosphate (δ) from various reptile remains recovered from China, Thailand, and Japan. δ values indicate that cold terrestrial climates prevailed at least in this part of Asia during the Barremian—early Albian interval. Estimated mean air temperatures of about 10 ± 4 °C at midlatitudes (∼42 °N) correspond to present day cool temperate climatic conditions. Such low temperatures are in agreement with previous reports of cold marine temperatures during this part of the Early Cretaceous, as well as with the widespread occurrence of the temperate fossil wood genus Xenoxylon and the absence of thermophilic reptiles such as crocodilians in northeastern China. The unique character of the Jehol Biota is thus not only the result of its evolutionary and biogeographical history but is also due to rather cold local climatic conditions linked to the paleolatitudinal position of northeastern China and global icehouse climates that prevailed during this part of the Early Cretaceous.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Conformations of p53 response elements in solution deduced using site-directed spin labeling and Monte Carlo sampling (2014)
    Oxford University Press
    Details
    Publication Date: 2014-02-28
    Description: The tumor suppressor protein p53 regulates numerous signaling pathways by specifically recognizing diverse p53 response elements (REs). Understanding the mechanisms of p53-DNA interaction requires structural information on p53 REs. However, such information is limited as a 3D structure of any RE in the unbound form is not available yet. Here, site-directed spin labeling was used to probe the solution structures of REs involved in p53 regulation of the p21 and Bax genes. Multiple nanometer distances in the p21-RE and BAX-RE, measured using a nucleotide-independent nitroxide probe and double-electron-electron-resonance spectroscopy, were used to derive molecular models of unbound REs from pools of all-atom structures generated by Monte-Carlo simulations, thus enabling analyses to reveal sequence-dependent DNA shape features of unbound REs in solution. The data revealed distinct RE conformational changes on binding to the p53 core domain, and support the hypothesis that sequence-dependent properties encoded in REs are exploited by p53 to achieve the energetically most favorable mode of deformation, consequently enhancing binding specificity. This work reveals mechanisms of p53-DNA recognition, and establishes a new experimental/computational approach for studying DNA shape in solution that has far-reaching implications for studying protein–DNA interactions.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    MSIsensor: microsatellite instability detection using paired tumor-normal sequence data (2014)
    Oxford University Press
    Details
    Publication Date: 2014-03-28
    Description: Motivation: Microsatellite instability (MSI) is an important indicator of larger genome instability and has been linked to many genetic diseases, including Lynch syndrome. MSI status is also an independent prognostic factor for favorable survival in multiple cancer types, such as colorectal and endometrial. It also informs the choice of chemotherapeutic agents. However, the current PCR–electrophoresis-based detection procedure is laborious and time-consuming, often requiring visual inspection to categorize samples. We developed MSIsensor, a C++ program for automatically detecting somatic microsatellite changes. It computes length distributions of microsatellites per site in paired tumor and normal sequence data, subsequently using these to statistically compare observed distributions in both samples. Comprehensive testing indicates MSIsensor is an efficient and effective tool for deriving MSI status from standard tumor-normal paired sequence data. Availability and implementation: https://github.com/ding-lab/msisensor Contact: kye@genome.wustl.edu or lding@genome.wustl.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 8
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    A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells (2015)
    Springer Nature
    Details
    Publication Date: 2015-03-13
    Description: A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells Cell Death and Disease 6, e1686 (March 2015). doi:10.1038/cddis.2015.25 Authors: B Chu, F Liu, L Li, C Ding, K Chen, Q Sun, Z Shen, Y Tan, C Tan & Y Jiang
    Electronic ISSN: 2041-4889
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 9
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    The 3DGD: a database of genome 3D structure (2014)
    Oxford University Press
    Details
    Publication Date: 2014-05-22
    Description: : The studies of chromatin 3D structure help us to understand its formation and function. Techniques combining chromosome conformation capture and next generation sequencing can capture chromatin structure information and has been applied to several different species and cell lines. We built 3DGD (3D Genome Database), a database that currently collected Hi-C data on four species, for easy accessing and visualization of chromatin 3D structure data. With the integration of other omics data such as genome-wide protein–DNA-binding data, this data source would be useful for researchers interested in chromatin structure and its biological functions. Availability and implementation: The 3DGD v1.1, data browser, downloadable files and documentation are available at: http://3dgd.biosino.org/ . Contact: cwang@sibs.ac.cn ; gwding@sibs.ac.cn ; yxli@sibs.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 10
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    A calcineurin- and NFAT-dependent pathway is involved in {alpha}-synuclein-induced degeneration of midbrain dopaminergic neurons (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-21
    Description: Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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