The histone deacetylase inhibitor Scriptaid targets G-quadruplexes Sánchez-Martín, Victoria Tello-López, María J. Ortiz-Morales, Andrea Murciano Calles, Javier García-Salcedo, José Antonio G-quadruplex Histone deacetylase inhibitors Transcription RNA polymerase I Colorectal cancer This study was funded by Ministry of Science and Innovation of Spain to J.A.G-S. (Instituto de Salud Carlos III (ISCIII), PI21/00497, co-funded by the European Union) and to M.S. (PID2020-120481RB-I00/AEI/10.13039/501100011033), by the local government Junta de Andalucía through PAIDI research groups (BIO-344) and by the Ministry of Science, Technological Development and Innovation of the Republic of Serbia (Grant Agreement with University of Belgrade-Faculty of Pharmacy No: 451‐03‐65/2024‐03/200161) to D.R. and K.N. The Government of Spain granted with PhD fellowship FPU16/05822 to V.S.-M. The University of Almeria granted with PhD fellowship CPRE2023-069 to M.J.T.-L. Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.7644194 Scriptaid is a chemical compound with anti-tumoural effects due to its role as a histone deacetylase inhibitor. Despite sharing part of the chemical structure with other ligands of G-quadruplexes (G4s), the interaction of Scriptaid with G4s has not been explored before. We synthesized Scriptaid and screened its cytotoxic activity in cellular models of colorectal cancer (CRC). We extensively evaluated its biological activity by cell cycle, immunofluorescence, qRT-PCR and Western blot experiments. To identify the G4 targets of Scriptaid, we conducted a panel of binding assays. Here, we show that Scriptaid induced cytotoxicity, cell cycle arrest and nucleolar stress in CRC cells. Moreover, Scriptaid impaired RNA polymerase I (Pol I) transcription, stabilized G4s and caused DNA damage. Finally, we disclose that these effects were attributable to the binding of Scriptaid to G4s in ribosomal DNA. In conclusion, our work reveals that a primary impact of Scriptaid on human cells is the interaction with G4s. 2025-03-11T08:59:21Z 2025-03-11T08:59:21Z 2025-02-19 journal article Sanchez-Martin V, Ruzic D, Tello-Lopez MJ, Ortiz-Morales A, Murciano-Calles J, Soriano M, Nikolic K, Garcia-Salcedo JA. 2025 The histone deacetylase inhibitor Scriptaid targets G-quadruplexes. Open Biol. 15: 240183. https://doi.org/10.1098/rsob.240183 https://hdl.handle.net/10481/102981 10.1098/rsob.240183 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Royal Society Publishing