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The Elongator complex is involved in the addition of 5'-carboxylmethyluridine (cm5U)-derived modifications to transfer RNAs (tRNAs), thereby influencing the translation of certain messenger RNAs (mRNAs) and helping to maintain the integrity of the proteome. This complex is involved in a variety of biological processes, and is of particular importance in oncology. The identification of chemical inhibitors of Elongator is of significant interest in both basic and pharmaceutical research.Through a yeast screen, this work reveals a potential new role for Elongator and identifies a chemical inhibitor of the complex. This compound presents itself as an interesting candidate as a pharmacological inhibitor, opening up new perspectives for the search for anti-cancer therapies.

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Abstract Radiotherapy is a cornerstone of cancer treatment and is currently administered to approximately half of all cancer patients. However, the cytotoxic effects of ionizing radiation on normal tissues represent a major limitation, as they restrict the dose that can be safely delivered to patients and, consequently, reduce the likelihood of effective tumor control. In this context, delivering radiation at ultra-high dose rates (UHDR, > 40 Gy/s) is gaining increasing attention due to its potential to spare healthy tissues surrounding the tumor and to prevent radiation-induced side effects, as compared to conventional dose rates (CONV, on the order of Gy/min).The mechanism underlying this protective effect-termed the FLASH effect-remains elusive, driving intensive research to elucidate the biological processes triggered by this type of irradiation.In vitro models offer a valuable tool to support this research, allowing for the efficient screening of various beam parameters and biological responses in a time- and cost-effective manner. In this study, multicellular tumor spheroids and normal cells were exposed to proton irradiation at UHDR to evaluate its efficacy in controlling tumor growth and its cytotoxic impact on healthy tissues, respectively.We report that UHDR and CONV irradiation induced a comparable growth delay in 3D tumor spheroids, suggesting similar efficacy in tumor control. In normal cells, both dose rates induced similar levels of senescence; however, UHDR irradiation led to lower apoptosis induction at clinically relevant doses and early time points post-irradiation.Taken together, these findings further highlight the potential of UHDR irradiation to modulate the response of normal tissues while maintaining comparable tumor control.JuryProf. Thomas BALLIGAND (UNamur), PresidentProf. Stéphane LUCAS (UNamur), SecretaryProf. Carine MICHIELS (UNamur)Dr Sébastien PENNINCKX (Hôpital Universitaire de Bruxelles)Prof. Cristian FERNANDEZ (University of Bern)Dr Rudi LABARBE (IBA)