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 and Bryce M. Paschal ()
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Chun-Song Yang: University of Virginia
Kasey Jividen: University of Virginia
Teddy Kamata: University of Virginia
Natalia Dworak: University of Virginia
Luke Oostdyk: University of Virginia
Bartlomiej Remlein: University of Virginia
Yasin Pourfarjam: Department of Chemistry, University of Cincinnati
In-Kwon Kim: Department of Chemistry, University of Cincinnati
Kang-Ping Du: Department of Radiation Oncology, University of Virginia
Tarek Abbas: University of Virginia
Nicholas E. Sherman: W. M. Keck Biomedical Mass Spectrometry Laboratory, University of Virginia
David Wotton: University of Virginia
Bryce M. Paschal: University of Virginia

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23055-6

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