The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation

Sarah El Kharraz, Vanessa Dubois, Martin E. van Royen, Adriaan B. Houtsmuller, Ekatarina Pavlova, Nina Atanassova, Tien Nguyen, Arnout Voet, Roy Eerlings, Florian Handle, Stefan Prekovic, Elien Smeets, Lisa Moris, Wout Devlies, Claes Ohlsson, Matti Poutanen, Kevin J. Verstrepen, Geert Carmeliet, Kaisa Mari Launonen, Laura HelminenJorma J. Palvimo, Claude Libert, Dirk Vanderschueren, Christine Helsen, Frank Claessens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Whereas dimerization of the DNA-binding domain of the androgen receptor (AR) plays an evident role in recognizing bipartite response elements, the contribution of the dimerization of the ligand-binding domain (LBD) to the correct functioning of the AR remains unclear. Here, we describe a mouse model with disrupted dimerization of the AR LBD (ARLmon/Y). The disruptive effect of the mutation is demonstrated by the feminized phenotype, absence of male accessory sex glands, and strongly affected spermatogenesis, despite high circulating levels of testosterone. Testosterone replacement studies in orchidectomized mice demonstrate that androgen-regulated transcriptomes in ARLmon/Y mice are completely lost. The mutated AR still translocates to the nucleus and binds chromatin, but does not bind to specific AR binding sites. In vitro studies reveal that the mutation in the LBD dimer interface also affects other AR functions such as DNA binding, ligand binding, and co-regulator binding. In conclusion, LBD dimerization is crucial for the development of AR-dependent tissues through its role in transcriptional regulation in vivo. Our findings identify AR LBD dimerization as a possible target for AR inhibition.

Original languageEnglish
Article numbere52764
JournalEMBO Reports
Volume22
Issue number12
DOIs
Publication statusPublished - 6 Dec 2021

Bibliographical note

Funding Information:
This work was funded by a research grant from the Flemish Fund for Scientific Research (FWO; 1131720N) and by a KU Leuven (grant C14/19/100). Sarah El Kharraz is a holder of a FWO aspirant fellowship (1131718N). BioID studies in the Palvimo laboratory were supported by UEF DPMM and Cancer Foundation Finland. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (Charlottesville, VA, USA) is supported by the Eunice Kennedy Shriver NICHD/NIH NCTRI) Grant P50‐HD28934. The authors thank Dieter Schollaert, Ludo Deboel, Hilde De Bruyn, Sofie De Block, Karen Moermans, and Erik van Herck for their technical assistance. Confocal imaging was performed with the support of University of Eastern Finland Cell and Tissue Imaging Unit. We thank the Laboratory of Markku Varjosalo (Institute of Biotechnology, University of Helsinki) for the BioID MS analysis.

Funding Information:
This work was funded by a research grant from the Flemish Fund for Scientific Research (FWO; 1131720N) and by a KU Leuven (grant C14/19/100). Sarah El Kharraz is a holder of a FWO aspirant fellowship (1131718N). BioID studies in the Palvimo laboratory were supported by UEF DPMM and Cancer Foundation Finland. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (Charlottesville, VA, USA) is supported by the Eunice Kennedy Shriver NICHD/NIH NCTRI) Grant P50-HD28934. The authors thank Dieter Schollaert, Ludo Deboel, Hilde De Bruyn, Sofie De Block, Karen Moermans, and Erik van Herck for their technical assistance. Confocal imaging was performed with the support of University of Eastern Finland Cell and Tissue Imaging Unit. We thank the Laboratory of Markku Varjosalo (Institute of Biotechnology, University of Helsinki) for the BioID MS analysis.

Publisher Copyright:
© 2021 The Authors

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