Proteomics

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An androgen signaling axis uses a writer and a reader of ADP-ribosylation to control protein complex assembly

ABSTRACT: Androgen signaling through the androgen receptor (AR) regulates multiple pathways in both normal and prostate cancer cells. Androgen regulates diverse aspects of the AR life cycle, including its post-translational modification, but understanding how specific modifications influence AR activity has been mostly elusive. Here, we show that androgen regulates AR through a pathway mediated by the mono-ADP ribosyltransferase, Parp7. We show that Parp7 ADP-ribosylates AR on multiple cysteines, and that a subset of these sites mediates agonist-specific recruitment of the E3 ligase Dtx3L/Parp9. Tandem macrodomains in Parp9 selectively recognize ADP ribosylated AR, and Dtx3L/Parp9 affects expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by 60 Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of a new androgen signaling axis that uses a writer and reader of ADP-ribosylation to modulate AR activity.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: JJ Park  

LAB HEAD: Bryce M. Paschal

PROVIDER: PXD018811 | Pride | 2021-05-28

REPOSITORIES: Pride

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Action DRS
Sampledescription.xlsx Xlsx
pR-AR_Chymotrypsin_PTM.sf3 Other
pR-AR_GluC_PTM.sf3 Other
pR-AR_Trypsin_PTM.sf3 Other
q190508q02.raw Raw
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Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly.

Yang Chun-Song CS   Jividen Kasey K   Kamata Teddy T   Dworak Natalia N   Oostdyk Luke L   Remlein Bartlomiej B   Pourfarjam Yasin Y   Kim In-Kwon IK   Du Kang-Ping KP   Abbas Tarek T   Sherman Nicholas E NE   Wotton David D   Paschal Bryce M BM  

Nature communications 20210511 1

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  ...[more]

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