Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly.
Chun-Song Yang, Kasey Jividen, Teddy Kamata, Natalia Dworak, Luke Oostdyk, Bartlomiej Remlein, Yasin Pourfarjam, In-Kwon Kim, Kang-Ping Du, Tarek Abbas, Nicholas E Sherman, David Wotton, Bryce M Paschal
Author Information
Chun-Song Yang: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Kasey Jividen: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Teddy Kamata: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Natalia Dworak: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Luke Oostdyk: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA. ORCID
Bartlomiej Remlein: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Yasin Pourfarjam: Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.
In-Kwon Kim: Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA. ORCID
Kang-Ping Du: Department of Radiation Oncology, University of Virginia, Charlottesville, VA, USA.
Tarek Abbas: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Nicholas E Sherman: W. M. Keck Biomedical Mass Spectrometry Laboratory, University of Virginia, Charlottesville, VA, USA.
David Wotton: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
Bryce M Paschal: Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA. paschal@virginia.edu. ORCID
Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.
