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

Autor: Teddy Kamata, Luke T. Oostdyk, Chun-Song Yang, In-Kwon Kim, Yasin Pourfarjam, Natalia Dworak, Kasey Jividen, Tarek Abbas, Bryce M. Paschal, Bartlomiej Remlein, Kang-Ping Du, David Wotton, Nicholas E. Sherman
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
medicine.drug_class
Science
Poly (ADP-Ribose) Polymerase-1
General Physics and Astronomy
Antineoplastic Agents
Protein complex assembly
Adenocarcinoma
Poly(ADP-ribose) Polymerase Inhibitors
General Biochemistry
Genetics and Molecular Biology
Piperazines
03 medical and health sciences
Prostate cancer
0302 clinical medicine
ADP-Ribosylation
Cell Line
Tumor
medicine
Humans
Protein Isoforms
Regulation of gene expression
Multidisciplinary
biology
Chemistry
Prostatic Neoplasms
General Chemistry
Metribolone
Androgen
medicine.disease
Survival Analysis
Ubiquitin ligase
Cell biology
Neoplasm Proteins
Androgen receptor
Gene Expression Regulation
Neoplastic
030104 developmental biology
Receptors
Androgen
030220 oncology & carcinogenesis
ADP-ribosylation
biology.protein
Phthalazines
Signal transduction
Poly(ADP-ribose) Polymerases
Protein Processing
Post-Translational
Signal Transduction
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021)
ISSN: 2041-1723
Popis: 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.
Databáze: OpenAIRE
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