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  1. Article ; Online: CDK activity at the centrosome regulates the cell cycle.

    Roberts, Emma L / Greenwood, Jessica / Kapadia, Nitin / Auchynnikava, Tania / Basu, Souradeep / Nurse, Paul

    Cell reports

    2024  Volume 43, Issue 4, Page(s) 114066

    Abstract: In human cells and yeast, an intact "hydrophobic patch" substrate docking site is needed for mitotic cyclin centrosomal localization. A hydrophobic patch mutant (HPM) of the fission yeast mitotic cyclin Cdc13 cannot enter mitosis, but whether this is due ...

    Abstract In human cells and yeast, an intact "hydrophobic patch" substrate docking site is needed for mitotic cyclin centrosomal localization. A hydrophobic patch mutant (HPM) of the fission yeast mitotic cyclin Cdc13 cannot enter mitosis, but whether this is due to defective centrosomal localization or defective cyclin-substrate docking more widely is unknown. Here, we show that artificially restoring Cdc13-HPM centrosomal localization promotes mitotic entry and increases CDK (cyclin-dependent kinase) substrate phosphorylation at the centrosome and in the cytoplasm. We also show that the S-phase B-cyclin hydrophobic patch is required for centrosomal localization but not for S phase. We propose that the hydrophobic patch is essential for mitosis due to its requirement for the local concentration of cyclin-CDK with CDK substrates and regulators at the centrosome. Our findings emphasize the central importance of the centrosome as a hub coordinating cell-cycle control and explain why the cyclin hydrophobic patch is essential for mitosis.
    MeSH term(s) Centrosome/metabolism ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Cyclin-Dependent Kinases/metabolism ; Cell Cycle ; Mitosis ; Phosphorylation ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/genetics ; Hydrophobic and Hydrophilic Interactions ; Humans ; Cyclin B
    Chemical Substances Schizosaccharomyces pombe Proteins ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Cdc13 protein, S pombe ; Cell Cycle Proteins ; Cyclin B
    Language English
    Publishing date 2024-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2024.114066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Skin Cancer Risk Is Increased by Somatic Mutations Detected Noninvasively in Healthy-Appearing Sun-Exposed Skin.

    Kaur, Kulvinder / Ai, Rizi / Perry, Allyson G / Riley, Bae / Roberts, Emma L / Montano, Erica N / Han, Jessica / Roacho, Joanna / Lopez, Brenda Garcia / Skelsey, Maral K / Childs, Maria V / Childs, James N / Dobak, John / Ibarra, Claudia / Jansen, Burkhard / Clarke, Loren E / Stone, Steven / Whitaker, John W

    The Journal of investigative dermatology

    2024  

    Abstract: Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic ... ...

    Abstract Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10
    Language English
    Publishing date 2024-03-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2024.02.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Hydrophobic Patch Directs Cyclin B to Centrosomes to Promote Global CDK Phosphorylation at Mitosis.

    Basu, Souradeep / Roberts, Emma L / Jones, Andrew W / Swaffer, Matthew P / Snijders, Ambrosius P / Nurse, Paul

    Current biology : CB

    2020  Volume 30, Issue 5, Page(s) 883–892.e4

    Abstract: The cyclin-dependent kinases (CDKs) are the major cell-cycle regulators that phosphorylate hundreds of substrates, controlling the onset of S phase and M phase [1-3]. However, the patterns of substrate phosphorylation increase are not uniform, as ... ...

    Abstract The cyclin-dependent kinases (CDKs) are the major cell-cycle regulators that phosphorylate hundreds of substrates, controlling the onset of S phase and M phase [1-3]. However, the patterns of substrate phosphorylation increase are not uniform, as different substrates become phosphorylated at different times as cells proceed through the cell cycle [4, 5]. In fission yeast, the correct ordering of CDK substrate phosphorylation can be established by the activity of a single mitotic cyclin-CDK complex [6, 7]. Here, we investigate the substrate-docking region, the hydrophobic patch, on the fission yeast mitotic cyclin Cdc13 as a potential mechanism to correctly order CDK substrate phosphorylation. We show that the hydrophobic patch targets Cdc13 to the yeast centrosome equivalent, the spindle pole body (SPB), and disruption of this motif prevents both centrosomal localization of Cdc13 and the onset of mitosis but does not prevent S phase. CDK phosphorylation in mitosis is compromised for approximately half of all mitotic CDK substrates, with substrates affected generally being those that require the highest levels of CDK activity to become phosphorylated and those that are located at the SPB. Our experiments suggest that the hydrophobic patch of mitotic cyclins contributes to CDK substrate selection by directing the localization of Cdc13-CDK to centrosomes and that this localization of CDK contributes to the CDK substrate phosphorylation necessary to ensure proper entry into mitosis. Finally, we show that mutation of the hydrophobic patch prevents cyclin B1 localization to centrosomes in human cells, suggesting that this mechanism of cyclin-CDK spatial regulation may be conserved across eukaryotes.
    MeSH term(s) Cell Line ; Centrosome/metabolism ; Cyclin B1/metabolism ; Cyclin-Dependent Kinases/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Phosphorylation ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism
    Chemical Substances CCNB1 protein, human ; Cyclin B1 ; Schizosaccharomyces pombe Proteins ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2020-02-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2019.12.053
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  4. Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.

    Canal, Berta / McClure, Allison W / Curran, Joseph F / Wu, Mary / Ulferts, Rachel / Weissmann, Florian / Zeng, Jingkun / Bertolin, Agustina P / Milligan, Jennifer C / Basu, Souradeep / Drury, Lucy S / Deegan, Tom D / Fujisawa, Ryo / Roberts, Emma L / Basier, Clovis / Labib, Karim / Beale, Rupert / Howell, Michael / Diffley, John F X

    The Biochemical journal

    2021  Volume 478, Issue 13, Page(s) 2445–2464

    Abstract: SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective ... ...

    Abstract SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
    MeSH term(s) Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Aurintricarboxylic Acid/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/metabolism ; Fluorescence ; High-Throughput Screening Assays ; Patulin/pharmacology ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism ; Viral Regulatory and Accessory Proteins/antagonists & inhibitors ; Viral Regulatory and Accessory Proteins/metabolism
    Chemical Substances Antiviral Agents ; NSP10 protein, SARS-CoV-2 ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Viral Regulatory and Accessory Proteins ; Aurintricarboxylic Acid (4431-00-9) ; Patulin (95X2BV4W8R) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-)
    Language English
    Publishing date 2021-07-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20210198
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase.

    Basu, Souradeep / Mak, Tiffany / Ulferts, Rachel / Wu, Mary / Deegan, Tom / Fujisawa, Ryo / Tan, Kang Wei / Lim, Chew Theng / Basier, Clovis / Canal, Berta / Curran, Joseph F / Drury, Lucy S / McClure, Allison W / Roberts, Emma L / Weissmann, Florian / Zeisner, Theresa U / Beale, Rupert / Cowling, Victoria H / Howell, Michael /
    Labib, Karim / Diffley, John F X

    The Biochemical journal

    2021  Volume 478, Issue 13, Page(s) 2481–2497

    Abstract: The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral ... ...

    Abstract The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2'-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir.
    MeSH term(s) Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Chlorobenzenes/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/genetics ; Exoribonucleases/isolation & purification ; Exoribonucleases/metabolism ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; Indazoles/pharmacology ; Indenes/pharmacology ; Indoles/pharmacology ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/genetics ; Methyltransferases/isolation & purification ; Methyltransferases/metabolism ; Nitriles/pharmacology ; Phenothiazines/pharmacology ; Purines/pharmacology ; RNA Caps/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Substrate Specificity ; Trifluperidol/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/isolation & purification ; Viral Nonstructural Proteins/metabolism ; Viral Regulatory and Accessory Proteins/genetics ; Viral Regulatory and Accessory Proteins/isolation & purification ; Viral Regulatory and Accessory Proteins/metabolism
    Chemical Substances Antiviral Agents ; Chlorobenzenes ; Indazoles ; Indenes ; Indoles ; NSP10 protein, SARS-CoV-2 ; NSP16 protein, SARS-CoV-2 ; Nitriles ; Phenothiazines ; Purines ; RNA Caps ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Viral Regulatory and Accessory Proteins ; inauzhin ; (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo(g)indazole-7-carboxylic acid (34ZKU73FU3) ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Methyltransferases (EC 2.1.1.-) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Alanine (OF5P57N2ZX) ; Trifluperidol (R8869Q7R8I) ; lomeguatrib (S79265T71M)
    Language English
    Publishing date 2021-06-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20210219
    Database MEDical Literature Analysis and Retrieval System OnLINE

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