Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly

Nat Commun. 2021 May 11;12(1):2705. doi: 10.1038/s41467-021-23055-6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-Ribosylation / drug effects
  • Adenocarcinoma
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Metribolone / pharmacology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational*
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Signal Transduction
  • Survival Analysis

Substances

  • AR protein, human
  • Antineoplastic Agents
  • Neoplasm Proteins
  • PARP9 protein, human
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Isoforms
  • Receptors, Androgen
  • Metribolone
  • PARP1 protein, human
  • PARP2 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • olaparib