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  1. Article ; Online: TOP1 and R-loops facilitate transcriptional DSBs at hypertranscribed cancer driver genes.

    Hidmi, Osama / Oster, Sara / Monin, Jonathan / Aqeilan, Rami I

    iScience

    2024  Volume 27, Issue 3, Page(s) 109082

    Abstract: ... we employ several techniques to map DSBs, R-loops, and topoisomerase 1 cleavage complex (TOP1cc ... to comprehensively investigate the interplay between transcription, DSBs, topoisomerase 1 (TOP1), and R-loops ... Our findings reveal the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops. Remarkably ...

    Abstract DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employ several techniques to map DSBs, R-loops, and topoisomerase 1 cleavage complex (TOP1cc) to comprehensively investigate the interplay between transcription, DSBs, topoisomerase 1 (TOP1), and R-loops. Our findings reveal the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops. Remarkably, transcription-associated DSBs at these loci are significantly reduced upon depletion of R-loops and TOP1, uncovering the pivotal roles of TOP1 and R-loops in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development, highlighting the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations.
    Language English
    Publishing date 2024-02-01
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2024.109082
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  2. Article ; Online: Correction: WWOX promotes osteosarcoma development via upregulation of Myc.

    Akkawi, Rania / Hidmi, Osama / Haj-Yahia, Ameen / Monin, Jonathon / Diment, Judith / Drier, Yotam / Stein, Gary S / Aqeilan, Rami I

    Cell death & disease

    2024  Volume 15, Issue 2, Page(s) 141

    Language English
    Publishing date 2024-02-14
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-024-06518-8
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  3. Article ; Online: WWOX promotes osteosarcoma development via upregulation of Myc.

    Akkawi, Rania / Hidmi, Osama / Haj-Yahia, Ameen / Monin, Jonathon / Diment, Judith / Drier, Yotam / Stein, Gary S / Aqeilan, Rami I

    Cell death & disease

    2024  Volume 15, Issue 1, Page(s) 13

    Abstract: Osteosarcoma is an aggressive bone tumor that primarily affects children and adolescents. This malignancy is highly aggressive, associated with poor clinical outcomes, and primarily metastasizes to the lungs. Due to its rarity and biological ... ...

    Abstract Osteosarcoma is an aggressive bone tumor that primarily affects children and adolescents. This malignancy is highly aggressive, associated with poor clinical outcomes, and primarily metastasizes to the lungs. Due to its rarity and biological heterogeneity, limited studies on its molecular basis exist, hindering the development of effective therapies. The WW domain-containing oxidoreductase (WWOX) is frequently altered in human osteosarcoma. Combined deletion of Wwox and Trp53 using Osterix1-Cre transgenic mice has been shown to accelerate osteosarcoma development. In this study, we generated a traceable osteosarcoma mouse model harboring the deletion of Trp53 alone (single-knockout) or combined deletion of Wwox/Trp53 (double-knockout) and expressing a tdTomato reporter. By tracking Tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow mesenchymal stem cells of non-osteosarcoma-bearing mice (young BM). We found that double-knockout young BM cells, but not single-knockout young BM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these double-knockout young BM cells revealed their resemblance to osteosarcoma tumor cells. Interestingly, one of the observed significant transcriptomic changes in double-knockout young BM cells was the upregulation of Myc and its target genes compared to single-knockout young BM cells. Intriguingly, Myc-chromatin immunoprecipitation sequencing revealed its increased enrichment on Myc targets, which were upregulated in double-knockout young BM cells. Restoration of WWOX in double-knockout young BM cells reduced Myc protein levels. As a prototype target, we demonstrated the upregulation of MCM7, a known Myc target, in double-knockout young BM relative to single-knockout young BM cells. Inhibition of MCM7 expression using simvastatin resulted in reduced proliferation and tumor cell growth of double-knockout young BM cells. Our findings reveal BM mesenchymal stem cells as a platform to study osteosarcoma and Myc and its targets as WWOX effectors and early molecular events during osteosarcomagenesis.
    MeSH term(s) Animals ; Humans ; Mice ; Bone Neoplasms/genetics ; Osteosarcoma/genetics ; Tumor Suppressor Proteins/genetics ; Up-Regulation/genetics ; WW Domain-Containing Oxidoreductase/genetics ; WW Domain-Containing Oxidoreductase/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism
    Chemical Substances tdTomato ; Tumor Suppressor Proteins ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-) ; Wwox protein, mouse (EC 1.1.1.-) ; Myc protein, mouse ; Proto-Oncogene Proteins c-myc
    Language English
    Publishing date 2024-01-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-06378-8
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  4. Article ; Online: Hippo signaling: to die or not to die.

    Aqeilan, R I

    Cell death and differentiation

    2013  Volume 20, Issue 10, Page(s) 1287–1288

    MeSH term(s) Animals ; Apoptosis/genetics ; DNA Damage ; Humans ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-abl/antagonists & inhibitors ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Tumor Suppressor Proteins ; LATS2 protein, human (EC 2.7.1.11) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2) ; Hippo protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2013-08-27
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/cdd.2013.100
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
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  5. Article: Real-Time Non-Invasive and Direct Determination of Lactate Dehydrogenase Activity in Cerebral Organoids-A New Method to Characterize the Metabolism of Brain Organoids?

    Sapir, Gal / Steinberg, Daniel J / Aqeilan, Rami I / Katz-Brull, Rachel

    Pharmaceuticals (Basel, Switzerland)

    2021  Volume 14, Issue 9

    Abstract: Organoids are a powerful tool in the quest to understand human diseases. As the developing brain is extremely inaccessible in mammals, cerebral organoids (COs) provide a unique way to investigate neural development and related disorders. The aim of this ... ...

    Abstract Organoids are a powerful tool in the quest to understand human diseases. As the developing brain is extremely inaccessible in mammals, cerebral organoids (COs) provide a unique way to investigate neural development and related disorders. The aim of this study was to utilize hyperpolarized
    Language English
    Publishing date 2021-08-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph14090878
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  6. Article: Current questions and controversies in chromosome fragile site research: does WWOX, the gene product of common fragile site FRA16D, have a passive or active role in cancer?

    Hazan, I / Aqeilan, R I

    Cell death discovery

    2015  Volume 1, Page(s) 15040

    Language English
    Publishing date 2015-10-19
    Publishing country United States
    Document type Journal Article
    ISSN 2058-7716
    ISSN 2058-7716
    DOI 10.1038/cddiscovery.2015.40
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  7. Article: Editorial: WW Domain Proteins in Signaling, Cancer Growth, Neural Diseases, and Metabolic Disorders.

    Chang, Nan-Shan / Lin, Rongtuan / Sze, Chun-I / Aqeilan, Rami I

    Frontiers in oncology

    2019  Volume 9, Page(s) 719

    Language English
    Publishing date 2019-08-02
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2019.00719
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  8. Article ; Online: WW domain interactions regulate the Hippo tumor suppressor pathway.

    Salah, Z / Aqeilan, R I

    Cell death & disease

    2011  Volume 2, Page(s) e172

    Abstract: The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the ... ...

    Abstract The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the upstream inputs, downstream outputs and regulation of the whole cascade. Enrichment of the Hippo pathway components with WW domains and their cognate proline-rich interacting motifs provides a versatile platform for further understanding the mechanisms that regulate organ growth and tumorigenesis. Here, we review recently discovered mechanisms of WW domain-mediated interactions that contribute to the regulation of the Hippo signaling pathway in tumorigenesis. We further discuss new insights and future directions on the emerging role of such regulation.
    MeSH term(s) Animals ; Humans ; Protein Interaction Domains and Motifs ; Protein-Serine-Threonine Kinases/chemistry ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Tumor Suppressor Proteins ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2011-06-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/cddis.2011.53
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  9. Article ; Online: Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation.

    Abu-Remaileh, M / Aqeilan, R I

    Cell death and differentiation

    2014  Volume 21, Issue 11, Page(s) 1805–1814

    Abstract: The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor ... ...

    Abstract The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1α (HIF1α) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1α and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1α levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism.
    MeSH term(s) Animals ; Cell Line, Tumor ; Genes, Tumor Suppressor ; Glucose/metabolism ; Glucose Transporter Type 1/metabolism ; Glycolysis ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Mitochondria/metabolism ; Oxidoreductases/metabolism ; Tumor Suppressor Proteins/metabolism ; WW Domain-Containing Oxidoreductase
    Chemical Substances Glucose Transporter Type 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Tumor Suppressor Proteins ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-) ; Wwox protein, mouse (EC 1.1.1.-) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2014-07-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/cdd.2014.95
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  10. Article ; Online: RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs.

    Machour, Feras E / Abu-Zhayia, Enas R / Awwad, Samah W / Bidany-Mizrahi, Tirza / Meinke, Stefan / Bishara, Laila A / Heyd, Florian / Aqeilan, Rami I / Ayoub, Nabieh

    Nucleic acids research

    2021  Volume 49, Issue 20, Page(s) 11708–11727

    Abstract: RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in ... ...

    Abstract RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/toxicity ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Line ; Cisplatin/therapeutic use ; Cisplatin/toxicity ; DNA Breaks, Double-Stranded ; Drug Resistance, Neoplasm ; Female ; HCT116 Cells ; Homologous Recombination ; Humans ; MCF-7 Cells ; Mammary Neoplasms, Experimental/drug therapy ; Mice ; Mice, SCID ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; RNA Stability ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Triple Negative Breast Neoplasms/metabolism
    Chemical Substances APBB1 protein, human ; Antineoplastic Agents ; Nerve Tissue Proteins ; Nuclear Proteins ; RBM6 protein, human ; RNA-Binding Proteins ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2021-11-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkab976
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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