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  1. Article ; Online: Centrosome Aberrations as Drivers of Chromosomal Instability in Breast Cancer.

    Piemonte, Katrina M / Anstine, Lindsey J / Keri, Ruth A

    Endocrinology

    2021  Volume 162, Issue 12

    Abstract: Chromosomal instability (CIN), or the dynamic change in chromosome number and composition, has been observed in cancer for decades. Recently, this phenomenon has been implicated as facilitating the acquisition of cancer hallmarks and enabling the ... ...

    Abstract Chromosomal instability (CIN), or the dynamic change in chromosome number and composition, has been observed in cancer for decades. Recently, this phenomenon has been implicated as facilitating the acquisition of cancer hallmarks and enabling the formation of aggressive disease. Hence, CIN has the potential to serve as a therapeutic target for a wide range of cancers. CIN in cancer often occurs as a result of disrupting key regulators of mitotic fidelity and faithful chromosome segregation. As a consequence of their essential roles in mitosis, dysfunctional centrosomes can induce and maintain CIN. Centrosome defects are common in breast cancer, a heterogeneous disease characterized by high CIN. These defects include amplification, structural defects, and loss of primary cilium nucleation. Recent studies have begun to illuminate the ability of centrosome aberrations to instigate genomic flux in breast cancer cells and the tumor evolution associated with aggressive disease and poor patient outcomes. Here, we review the role of CIN in breast cancer, the processes by which centrosome defects contribute to CIN in this disease, and the emerging therapeutic approaches that are being developed to capitalize upon such aberrations.
    MeSH term(s) Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Centrosome/metabolism ; Centrosome/pathology ; Centrosome/physiology ; Chromosomal Instability/genetics ; Female ; Genomic Instability/genetics ; Humans
    Language English
    Publishing date 2021-10-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqab208
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction.

    Piemonte, Katrina M / Webb, Bryan M / Bobbitt, Jessica R / Majmudar, Parth R / Cuellar-Vite, Leslie / Bryson, Benjamin L / Latina, Nicholas C / Seachrist, Darcie D / Keri, Ruth A

    The Journal of biological chemistry

    2023  Volume 299, Issue 7, Page(s) 104834

    Abstract: Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. ...

    Abstract Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. While it is well established that sustained condensin expression is necessary to ensure chromosome stability, the mechanisms that control its expression are not yet known. Herein, we report that disruption of cyclin-dependent kinase 7 (CDK7), the core catalytic subunit of CDK-activating kinase, leads to reduced transcription of several condensin subunits, including structural maintenance of chromosomes 2 (SMC2). Live and static microscopy revealed that inhibiting CDK7 signaling prolongs mitosis and induces chromatin bridge formation, DNA double-strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Affirming the importance of condensin regulation by CDK7, genetic suppression of the expression of SMC2, a core subunit of this complex, phenocopies CDK7 inhibition. Moreover, analysis of genome-wide chromatin conformation using Hi-C revealed that sustained activity of CDK7 is necessary to maintain chromatin sublooping, a function that is ascribed to condensin. Notably, the regulation of condensin subunit gene expression is independent of superenhancers. Together, these studies reveal a new role for CDK7 in sustaining chromatin configuration by ensuring the expression of condensin genes, including SMC2.
    MeSH term(s) Chromatin/genetics ; Chromatin/metabolism ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Mitosis/genetics ; Chromosomal Instability/genetics ; Signal Transduction ; Humans ; Cell Line, Tumor ; Gene Expression Regulation/genetics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Gene Silencing
    Chemical Substances Chromatin ; condensin complexes ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; CDK7 protein, human ; SMC2 protein, human ; Cell Cycle Proteins
    Language English
    Publishing date 2023-05-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104834
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance.

    Roberts, Melyssa S / Sahni, Jennifer M / Schrock, Morgan S / Piemonte, Katrina M / Weber-Bonk, Kristen L / Seachrist, Darcie D / Avril, Stefanie / Anstine, Lindsey J / Singh, Salendra / Sizemore, Steven T / Varadan, Vinay / Summers, Matthew K / Keri, Ruth A

    Cancer research

    2020  Volume 80, Issue 8, Page(s) 1693–1706

    Abstract: A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer ( ... ...

    Abstract A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of
    MeSH term(s) Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Line, Tumor ; Cellular Senescence ; Centrosome/enzymology ; Drug Resistance, Neoplasm/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Heterografts ; Humans ; Mitosis/drug effects ; Mitosis/genetics ; NIMA-Related Kinases/antagonists & inhibitors ; NIMA-Related Kinases/metabolism ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/metabolism ; Paclitaxel/administration & dosage ; Paclitaxel/pharmacology ; Survival Rate ; Taxoids/administration & dosage ; Taxoids/pharmacology ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/mortality ; Tumor Stem Cell Assay ; Tumor Suppressor Proteins/antagonists & inhibitors ; Tumor Suppressor Proteins/metabolism ; Up-Regulation
    Chemical Substances Antineoplastic Agents ; LIN9 protein, human ; Neoplasm Proteins ; Nuclear Proteins ; Taxoids ; Tumor Suppressor Proteins ; NEK2 protein, human (EC 2.7.11.1) ; NIMA-Related Kinases (EC 2.7.11.1) ; Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2020-02-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-19-3466
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Structure determination of BA0150, a putative polysaccharide deacetylase from Bacillus anthracis.

    Strunk, Robert J / Piemonte, Katrina M / Petersen, Natasha M / Koutsioulis, Dimitris / Bouriotis, Vassilis / Perry, Kay / Cole, Kathryn E

    Acta crystallographica. Section F, Structural biology communications

    2014  Volume 70, Issue Pt 2, Page(s) 156–159

    Abstract: Polysaccharide deacetylases are bacterial enzymes that catalyze the deacetylation of acetylated sugars on the membranes of Gram-positive bacteria, allowing them to be unrecognized by host immune systems. Inhibition of these enzymes would disrupt such ... ...

    Abstract Polysaccharide deacetylases are bacterial enzymes that catalyze the deacetylation of acetylated sugars on the membranes of Gram-positive bacteria, allowing them to be unrecognized by host immune systems. Inhibition of these enzymes would disrupt such pathogenic defensive mechanisms and therefore offers a promising route for the development of novel antibiotic therapeutics. Here, the first X-ray crystal structure of BA0150, a putative polysaccharide deacetylase from Bacillus anthracis, is reported to 2.0 Å resolution. The overall structure maintains the conserved (α/β)8 fold that is characteristic of this family of enzymes. The lack of a catalytic metal ion and a distinctive metal-binding site, however, suggest that this enzyme is not a functional polysaccharide deacetylase.
    MeSH term(s) Amidohydrolases/chemistry ; Amino Acid Sequence ; Bacillus anthracis/enzymology ; Crystallography, X-Ray ; Molecular Sequence Data ; Protein Conformation ; Sequence Homology, Amino Acid ; Spectrometry, X-Ray Emission
    Chemical Substances Amidohydrolases (EC 3.5.-) ; polysaccharide deacetylase (EC 3.5.1.-)
    Language English
    Publishing date 2014-01-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2053-230X
    ISSN (online) 2053-230X
    DOI 10.1107/S2053230X13034262
    Database MEDical Literature Analysis and Retrieval System OnLINE

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