Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 9100095 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9327 (Electronic) Linking ISSN: 10447431 NLM ISO Abbreviation: Mol Cell Neurosci Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Diego : Academic Press, c1990-
    • Subject Terms:
      Amyloid Precursor Protein Secretases*/metabolism ; Amyloid beta-Protein Precursor*/metabolism; Nuclear Proteins/metabolism ; Carrier Proteins/metabolism ; DNA Repair
    • Abstract:
      Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following β- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different α-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon γ-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) α-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of α-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that α-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.
      Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
      (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Alpha-secretase; Alzheimer's disease; Amyloid-β precursor protein; DNA repair; Fe65
    • Accession Number:
      EC 3.4.- (Amyloid Precursor Protein Secretases)
      0 (Amyloid beta-Protein Precursor)
      0 (Nuclear Proteins)
      0 (Carrier Proteins)
    • Publication Date:
      Date Created: 20231102 Date Completed: 20231206 Latest Revision: 20231206
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.mcn.2023.103903
    • Accession Number:
      37918552