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Lookup NU author(s): Shangze Xu, Matthew Kondal, Dr Ayaz Ayaz, Dr Ruidi Zhu, Lanyu Fan, Dr Piotr Zaborniak, Dr Kate HarrisORCiD, Joao Victor de De Souza Cunha, Dr Agnieszka Bronowska
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 by the authors.The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR’s constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.
Author(s): Xu S, Kondal MD, Ahmad A, Zhu R, Fan L, Zaborniak P, Madden KS, de Souza JV, Bronowska AK
Publication type: Article
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2023
Volume: 24
Issue: 2
Print publication date: 02/01/2023
Online publication date: 09/01/2023
Acceptance date: 30/12/2022
Date deposited: 07/02/2023
ISSN (print): 1661-6596
ISSN (electronic): 1422-0067
Publisher: MDPI
URL: https://doi.org/10.3390/ijms24021270
DOI: 10.3390/ijms24021270
PubMed id: 36674785
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