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  1. Article ; Online: XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition

    Praveen L. Patidar / Talysa Viera / Julio C. Morales / Naveen Singh / Edward A. Motea / Megha Khandelwal / Farjana J. Fattah

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Abstract Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, ... ...

    Abstract Abstract Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2’s association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors

    Yan, Yunfeng / Kejin Zhou / Hu Xiong / Jason B. Miller / Edward A. Motea / David A. Boothman / Li Liu / Daniel J. Siegwart

    Biomaterials. 2017 Feb., v. 118

    2017  

    Abstract: Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) ... ...

    Abstract Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) readily accumulate in the liver after intravenous (i.v.) administration. Delivering RNAs to other organs and tumor tissues remains an ongoing challenge. Here, we utilized a 540-member combinatorial functional polyester library to discover nanoparticles (NPs) that enable efficacious siRNA delivery to A549 lung cancer cells in vitro and in vivo. PE4K-A13–0.33C6 and PE4K-A13–0.33C10 NPs were efficiently internalized into A549-Luc cells within 4 h. The addition of PEG 2000 DMG lipid or Pluronic F-127 onto the surface of the polyplexes reduced the surface charge of NPs, resulting in an increase of serum stability. We then explored aerosol delivery of stabilized PE4K-A13–0.33C6 and PE4K-A13–0.33C10 NPs to implanted orthotopic lung tumors. We found that by altering the administration route from i.v. to aerosol, the NPs could avoid liver accumulation and instead be specifically localized only in the lungs. This resulted in significant gene silencing in the A549 orthotopic lung tumors. Due to the ability to deliver siRNA to non-liver targets, this approach provides a privileged route for gene silencing in the lungs.
    Keywords aerosols ; blood serum ; gene expression ; gene silencing ; intravenous injection ; lipids ; liver ; lung neoplasms ; lungs ; nanoparticles ; neoplasm cells ; polyesters ; small interfering RNA ; therapeutics ; tissues
    Language English
    Dates of publication 2017-02
    Size p. 84-93.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 603079-8
    ISSN 0142-9612
    ISSN 0142-9612
    DOI 10.1016/j.biomaterials.2016.12.001
    Database NAL-Catalogue (AGRICOLA)

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