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

doi:10.1038/s41467-021-23055-6

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.

Authors

Chun-Song Yang^{1

2}, Kasey Jividen¹, Teddy Kamata^{1

2}, Natalia Dworak¹, Luke Oostdyk^{1

2}, Bartlomiej Remlein^{1

2}, Yasin Pourfarjam³, In-Kwon Kim³, Kang-Ping Du⁴, Tarek Abbas^{1

2

4}, Nicholas E Sherman⁵, David Wotton^{1

2}, Bryce M Paschal^{6

7}

Affiliations

¹ Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
² Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
³ Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.
⁴ Department of Radiation Oncology, University of Virginia, Charlottesville, VA, USA.
⁵ W. M. Keck Biomedical Mass Spectrometry Laboratory, University of Virginia, Charlottesville, VA, USA.
⁶ Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA. paschal@virginia.edu.
⁷ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA. paschal@virginia.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding