title: Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation.
abstract: Steroidogenic factor 1 (SF-1 or NR5A1) is a nuclear receptor that controls adrenogenital cell growth and differentiation. Adrenogenital primordial cells from SF-1 knockout mice die of apoptosis, but the mechanism by which SF-1 regulates cell survival is not entirely clear. Besides functioning in the nucleus, SF-1 also resides in the centrosome and controls centrosome homeostasis. Here, we show that SF-1 restricts centrosome overduplication by inhibiting aberrant activation of DNA-dependent protein kinase (DNA-PK) in the centrosome. SF-1 was found to be associated with Ku70/Ku80 only in the centrosome, sequestering them from the catalytic subunit of DNA-PK (DNA-PKcs). In the absence of SF-1, DNA-PKcs was recruited to the centrosome and activated, causing aberrant activation of centrosomal Akt and cyclin-dependent kinase 2 (CDK2)/cyclin A and leading to centrosome overduplication. Centrosome overduplication caused by SF-1 depletion was averted by the elimination of DNA-PKcs, Ku70/80, or cyclin A or by the inhibition of CDK2 or Akt. In the nucleus, SF-1 did not interact with Ku70/80, and SF-1 depletion did not activate a nuclear DNA damage response. Centriole biogenesis was also unaffected. Thus, centrosomal DNA-PK signaling triggers centrosome overduplication, and this centrosomal event, but not the nuclear DNA damage response, is controlled by SF-1.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yih
authors.initials: CY
authors.lastname: Wang
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Kao
authors.forename: Pao-Yen
authors.initials: PY
authors.lastname: Lai
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.forename: Bon-chu
authors.initials: BC
authors.lastname: Chung
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D000072200:Ku Autoantigen; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D019925:Cyclin A; D004268:DNA-Binding Proteins; D054339:Steroidogenic Factor 1; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen