Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors

Abstract Human topoisomerase IIβ binding protein 1 (TopBP1) is a scaffold protein involved in DNA replication initiation, DNA repair, transcription regulation, and checkpoint activation. TopBP1 forms nuclear condensates that act as a molecular switch to amplify ATR activity and promote the activatio...

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Veröffentlicht in:	NAR cancer Jg. 7; H. 4; S. zcaf041
Hauptverfasser:	Morano, Laura, Vie, Nadia, Aissanou, Adam, Hodroj, Dana, Garambois, Véronique, Fauvre, Alexandra, Promonet, Alexy, Egger, Tom, Bordignon, Benoît, Hassen-Khodja, Cédric, Fiachetti, Solène, Basbous, Jihane, Gongora, Céline, Constantinou, Angelos
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England Oxford University Press 01.12.2025
Schlagworte:	5-Fluorouracil Animals Antineoplastic Agents - pharmacology Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors Ataxia Telangiectasia Mutated Proteins - metabolism Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line, Tumor Checkpoint Kinase 1 - metabolism Chemotherapy CHK1 protein Chromatin Clinical trials Colorectal carcinoma Condensates DNA biosynthesis DNA repair DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Discovery - methods Drug resistance Fluorouracil - administration & dosage Fluorouracil - pharmacology Gene regulation High-throughput screening High-Throughput Screening Assays - methods Humans Irinotecan Irinotecan - pharmacology Kinases Mice Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - genetics Nuclear Proteins - metabolism Quinacrine Replication initiation Signal Transduction - drug effects Thimerosal Toxicity Transcription activation Transcription initiation
ISSN:	2632-8674, 2632-8674
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Zusammenfassung:	Abstract Human topoisomerase IIβ binding protein 1 (TopBP1) is a scaffold protein involved in DNA replication initiation, DNA repair, transcription regulation, and checkpoint activation. TopBP1 forms nuclear condensates that act as a molecular switch to amplify ATR activity and promote the activation of the checkpoint effector kinase Chk1. In cancer cells, ATR activity is crucial to tolerate the intrinsically high level of DNA lesions and obstacles that block replication fork progression. Thus, ATR inhibitors are currently tested in clinical trials, often in combination with chemotherapy drugs. However, resistance and toxicity are still major issues. The weak interactions that hold TopBP1 condensates together are highly sensitive to changes in the cellular milieu, suggesting that small molecules may alter the formation of TopBP1 condensates. Here, we developed a high-throughput screening system to identify TopBP1 condensation modulators. This system allowed us to identify FDA-approved drugs, including thimerosal and quinacrine, that inhibit TopBP1 condensation and block the activation of ATR/Chk1 signaling. Mechanistically, quinacrine impaired TopBP1’s ability to associate with chromatin, thereby interfering with its capacity to form condensates. Furthermore, quinacrine enhanced the therapeutic efficacy of 5-fluorouracil and irinotecan, components of the clinically used FOLFIRI regimen in a mouse model of peritoneal carcinomatosis from colorectal cancer. Graphical Abstract Graphical Abstract
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2632-8674 2632-8674
DOI:	10.1093/narcan/zcaf041