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Mol. Cell. Biol. 33 (3): 476-484

Copyright © 2013 by the American Society for Microbiology. All rights reserved.

Steroidogenic Factor 1 (NR5A1) Maintains Centrosome Homeostasis in Steroidogenic Cells by Restricting Centrosomal DNA-Dependent Protein Kinase Activation

Chia-Yih Wang,a Yung-Hsin Kao,a,b Pao-Yen Lai,a Wei-Yi Chen,a,*, and Bon-chu Chunga

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan,a Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan,b

Received for publication 3 August 2012. Revision received 2 September 2012. Accepted for publication 5 November 2012.

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.

Address correspondence to Bon-chu Chung, mbchung{at}

* Present address: Wei-Yi Chen, Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York, USA.

Published ahead of print 19 November 2012

Supplemental material for this article may be found at

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