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  1. Article ; Online: Use of CRISPR/Cas9 with Homology-Directed Repair to Gene-Edit Topoisomerase II

    Carvajal-Moreno, Jessika / Wang, Xinyi / Hernandez, Victor A / Mondal, Milon / Zhao, Xinyu / Yalowich, Jack C / Elton, Terry S

    The Journal of pharmacology and experimental therapeutics

    2024  Volume 389, Issue 2, Page(s) 186–196

    Abstract: DNA topoisomerase ... ...

    Abstract DNA topoisomerase II
    MeSH term(s) Humans ; Etoposide/pharmacology ; K562 Cells ; DNA Topoisomerases, Type II/genetics ; DNA Topoisomerases, Type II/metabolism ; Mitoxantrone ; CRISPR-Cas Systems/genetics ; Codon, Nonsense ; Antineoplastic Agents/pharmacology ; Leukemia ; DNA ; Phenotype
    Chemical Substances Etoposide (6PLQ3CP4P3) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Mitoxantrone (BZ114NVM5P) ; Codon, Nonsense ; Antineoplastic Agents ; DNA (9007-49-2)
    Language English
    Publishing date 2024-04-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.123.002038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.

    Mann, Chelsea A / Carvajal Moreno, Jessika J / Lu, Yanran / Dellos-Nolan, Sheri / Wozniak, Daniel J / Yalowich, Jack C / Mitton-Fry, Mark J

    Antimicrobial agents and chemotherapy

    2023  Volume 67, Issue 10, Page(s) e0048223

    Abstract: Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique ... ...

    Abstract Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated by
    MeSH term(s) Humans ; Topoisomerase Inhibitors/pharmacology ; DNA Gyrase/metabolism ; DNA Topoisomerase IV ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/chemistry ; Staphylococcus aureus/metabolism ; DNA ; Amides/pharmacology ; Topoisomerase II Inhibitors/pharmacology ; Microbial Sensitivity Tests
    Chemical Substances Topoisomerase Inhibitors ; DNA Gyrase (EC 5.99.1.3) ; DNA Topoisomerase IV (EC 5.99.1.-) ; Anti-Bacterial Agents ; DNA (9007-49-2) ; Amides ; Topoisomerase II Inhibitors
    Language English
    Publishing date 2023-09-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/aac.00482-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: Use of CRISPR/Cas9 with homology-directed repair to silence the human topoisomerase IIα intron-19 5' splice site: Generation of etoposide resistance in human leukemia K562 cells.

    Hernandez, Victor A / Carvajal-Moreno, Jessika / Wang, Xinyi / Pietrzak, Maciej / Yalowich, Jack C / Elton, Terry S

    PloS one

    2022  Volume 17, Issue 5, Page(s) e0265794

    Abstract: DNA Topoisomerase IIα (TOP2α/170) is an enzyme essential for proliferating cells. For rapidly multiplying malignancies, this has made TOP2α/170 an important target for etoposide and other clinically active anticancer drugs. Efficacy of these agents is ... ...

    Abstract DNA Topoisomerase IIα (TOP2α/170) is an enzyme essential for proliferating cells. For rapidly multiplying malignancies, this has made TOP2α/170 an important target for etoposide and other clinically active anticancer drugs. Efficacy of these agents is often limited by chemoresistance related to alterations in TOP2α/170 expression levels. Our laboratory recently demonstrated reduced levels of TOP2α/170 and overexpression of a C-terminal truncated 90-kDa isoform, TOP2α/90, due to intronic polyadenylation (IPA; within intron 19) in an acquired etoposide-resistant K562 clonal cell line, K/VP.5. We previously reported that this isoform heterodimerized with TOP2α/170 and was a determinant of acquired resistance to etoposide. Optimization of the weak TOP2α exon 19/intron 19 5' splice site in drug-resistant K/VP.5 cells by gene-editing restored TOP2α/170 levels, diminished TOP2α/90 expression, and circumvented drug resistance. Conversely, in the present study, silencing of the exon 19/intron 19 5' splice site in parental K562 cells by CRISPR/Cas9 with homology-directed repair (HDR), and thereby forcing intron 19 retention, was used to induce resistance by disrupting normal RNA processing (i.e., gene knockout), and to further evaluate the role of TOP2α/170 and TOP2α/90 isoforms as resistance determinants. Gene-edited clones were identified by quantitative polymerase chain reaction (qPCR) and verified by Sanger sequencing. TOP2α/170 mRNA/protein expression levels were attenuated in the TOP2α gene-edited clones which resulted in resistance to etoposide as assessed by reduced etoposide-induced DNA damage (γH2AX, Comet assays) and growth inhibition. RNA-seq and qPCR studies suggested that intron 19 retention leads to decreased TOP2α/170 expression by degradation of the TOP2α edited mRNA transcripts. Forced expression of TOP2α/90 in the gene-edited K562 cells further decreased etoposide-induced DNA damage in support of a dominant negative role for this truncated isoform. Together results support the important role of both TOP2α/170 and TOP2α/90 as determinants of sensitivity/resistance to TOP2α-targeting agents.
    MeSH term(s) Antigens, Neoplasm/genetics ; CRISPR-Cas Systems/genetics ; DNA Topoisomerases, Type II/genetics ; DNA Topoisomerases, Type II/metabolism ; Etoposide/pharmacology ; Humans ; Introns/genetics ; K562 Cells ; Leukemia/genetics ; RNA Splice Sites ; RNA, Messenger
    Chemical Substances Antigens, Neoplasm ; RNA Splice Sites ; RNA, Messenger ; Etoposide (6PLQ3CP4P3) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0265794
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Intronic Polyadenylation in Acquired Cancer Drug Resistance Circumvented by Utilizing CRISPR/Cas9 with Homology-Directed Repair: The Tale of Human DNA Topoisomerase IIα.

    Elton, Terry S / Hernandez, Victor A / Carvajal-Moreno, Jessika / Wang, Xinyi / Ipinmoroti, Deborah / Yalowich, Jack C

    Cancers

    2022  Volume 14, Issue 13

    Abstract: Intronic polyadenylation (IPA) plays a critical role in malignant transformation, development, progression, and cancer chemoresistance by contributing to transcriptome/proteome alterations. DNA topoisomerase IIα (170 kDa, TOP2α/170) is an established ... ...

    Abstract Intronic polyadenylation (IPA) plays a critical role in malignant transformation, development, progression, and cancer chemoresistance by contributing to transcriptome/proteome alterations. DNA topoisomerase IIα (170 kDa, TOP2α/170) is an established clinical target for anticancer agents whose efficacy is compromised by drug resistance often associated with a reduction of nuclear TOP2α/170 levels. In leukemia cell lines with acquired resistance to TOP2α-targeted drugs and reduced TOP2α/170 expression, variant TOP2α mRNA transcripts have been reported due to IPA that resulted in the translation of C-terminal truncated isoforms with altered nuclear-cytoplasmic distribution or heterodimerization with wild-type TOP2α/170. This review provides an overview of the various mechanisms regulating pre-mRNA processing and alternative polyadenylation, as well as the utilization of CRISPR/Cas9 specific gene editing through homology directed repair (HDR) to decrease IPA when splice sites are intrinsically weak or potentially mutated. The specific case of TOP2α exon 19/intron 19 splice site editing is discussed in etoposide-resistant human leukemia K562 cells as a tractable strategy to circumvent acquired TOP2α-mediated drug resistance. This example supports the importance of aberrant IPA in acquired drug resistance to TOP2α-targeted drugs. In addition, these results demonstrate the therapeutic potential of CRISPR/Cas9/HDR to impact drug resistance associated with aberrant splicing/polyadenylation.
    Language English
    Publishing date 2022-06-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14133148
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Effects of hsa-miR-9-3p and hsa-miR-9-5p on Topoisomerase II

    Carvajal-Moreno, Jessika / Hernandez, Victor A / Wang, Xinyi / Li, Junan / Yalowich, Jack C / Elton, Terry S

    The Journal of pharmacology and experimental therapeutics

    2022  Volume 384, Issue 2, Page(s) 265–276

    Abstract: DNA topoisomerase ... ...

    Abstract DNA topoisomerase II
    MeSH term(s) Humans ; Antineoplastic Agents/pharmacology ; DNA Topoisomerases, Type II/genetics ; DNA Topoisomerases, Type II/metabolism ; Etoposide/pharmacology ; K562 Cells ; Leukemia ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Messenger
    Chemical Substances Antineoplastic Agents ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Etoposide (6PLQ3CP4P3) ; MicroRNAs ; MIRN92 microRNA, human ; RNA, Messenger ; TOP2B protein, human (EC 5.99.1.3)
    Language English
    Publishing date 2022-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.122.001429
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  6. Article ; Online: CRISPR/Cas9 Genome Editing of the Human Topoisomerase II

    Hernandez, Victor A / Carvajal-Moreno, Jessika / Papa, Jonathan L / Shkolnikov, Nicholas / Li, Junan / Ozer, Hatice Gulcin / Yalowich, Jack C / Elton, Terry S

    Molecular pharmacology

    2021  Volume 99, Issue 3, Page(s) 226–241

    Abstract: An essential function of DNA topoisomerase ... ...

    Abstract An essential function of DNA topoisomerase II
    MeSH term(s) CRISPR-Cas Systems ; Cell Survival ; DNA Topoisomerases, Type II/genetics ; Down-Regulation ; Drug Resistance, Neoplasm ; Etoposide/pharmacology ; Gene Editing/methods ; Humans ; Introns ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Poly-ADP-Ribose Binding Proteins/genetics ; RNA Splice Sites
    Chemical Substances Poly-ADP-Ribose Binding Proteins ; RNA Splice Sites ; Etoposide (6PLQ3CP4P3) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; TOP2A protein, human (EC 5.99.1.3)
    Language English
    Publishing date 2021-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/molpharm.120.000173
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: hsa-miR-9-3p and hsa-miR-9-5p as Post-Transcriptional Modulators of DNA Topoisomerase II

    Kania, Evan E / Carvajal-Moreno, Jessika / Hernandez, Victor A / English, Anthony / Papa, Jonathan L / Shkolnikov, Nicholas / Ozer, Hatice Gulcin / Yilmaz, Ayse Selen / Yalowich, Jack C / Elton, Terry S

    Molecular pharmacology

    2019  Volume 97, Issue 3, Page(s) 159–170

    Abstract: DNA topoisomerase ... ...

    Abstract DNA topoisomerase II
    MeSH term(s) Antineoplastic Agents, Phytogenic/pharmacology ; DNA Topoisomerases, Type II/biosynthesis ; DNA Topoisomerases, Type II/genetics ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Etoposide/pharmacology ; Humans ; K562 Cells ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; Transcription, Genetic/drug effects ; Transcription, Genetic/physiology
    Chemical Substances Antineoplastic Agents, Phytogenic ; MIRN93 microRNA, human ; MIRN95 microRNA, human ; MicroRNAs ; Etoposide (6PLQ3CP4P3) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
    Language English
    Publishing date 2019-12-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.119.118315
    Database MEDical Literature Analysis and Retrieval System OnLINE

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