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Biochimie. 2019 Dec;167:187-197. doi: 10.1016/j.biochi.2019.09.016. Epub 2019 Sep 25.

Interactions of the Rad51 inhibitor DIDS with human and bovine serum albumins: Optical spectroscopy and isothermal calorimetry approaches.

Author information

1
Group of Mechanism and Regulation of DNA Repair and IMPACT Platform, UFIP UMR CNRS 6286, University of Nantes, 44322, Nantes, France; Centre de Recherche en Cancérologie de l'Université Laval, Laboratoire de Stabilité du Génome, 9, rue McMahon, G1R 3S3, Québec, Canada.
2
Group of Mechanism and Regulation of DNA Repair and IMPACT Platform, UFIP UMR CNRS 6286, University of Nantes, 44322, Nantes, France.
3
Laboratoire CEISAM - UMR CNR 6230, Université de Nantes, 2 Rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
4
Centre de Recherche en Cancérologie de l'Université Laval, Laboratoire de Stabilité du Génome, 9, rue McMahon, G1R 3S3, Québec, Canada.
5
Laboratoire de Recherche en Nanosciences EA4682-LRB, Université de Reims Champagne-Ardenne, 51100, Reims, France; National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), 31 Kashirskoe Shosse, 115522, Moscow, Russian Federation; Department of Clinical Immunology and Allergology, Sechenov First Moscow State Medical University, 119992, Moscow, Russian Federation.
6
Group of Mechanism and Regulation of DNA Repair and IMPACT Platform, UFIP UMR CNRS 6286, University of Nantes, 44322, Nantes, France. Electronic address: fleury-f@univ-nantes.fr.

Abstract

Rad51 is a key protein in DNA repair by homologous recombination and an important target for development of drugs in cancer therapy. 4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) has been used in clinic during the past 30 years as an inhibitor of anion transporters and channels. Recently DIDS has been demonstrated to affect Rad51-mediated homologous pairing and strand exchange, key processes in homologous recombination. Consequently, DIDS has been considered as a potential revertant of radio- and chemo-resistance of cancer cells, the major causes of therapy failure. Here, we have investigated the behavior of DIDS towards serum albumins. The effects of environmental factors, primarily, solvent polarity, on DIDS stability were evaluated, and the mechanisms of interaction of DIDS with human or bovine serum albumin were analyzed using isothermal calorimetry, circular dichroism and fluorescence spectroscopies. DIDS interaction with both serum albumins have been demonstrated, and the interaction characteristics have been determined. By comparing these characteristics for several DIDS derivatives, we have identified the DIDS moiety essential for the interaction. Furthermore, site competition data indicate that human albumin has two DIDS-binding sites: a high-affinity site in the IIIA subdomain and a low-affinity one in the IB subdomain. Molecular docking has revealed the key molecular moieties of DIDS responsible for its interactions in each site and shown that the IB site can bind two ligands. These findings show that binding of DIDS to serum albumin may change the balance between the free and bound DIDS forms, thereby affecting its bioavailability and efficacy against Rad51.

KEYWORDS:

Blood albumin; DNA repair; Protein-ligand interaction; Stilbene inhibitors

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