Molecular characterisation of Toxoplasma gondii Mre11 reveals unique structural features and potential as a therapeutic target

Abstract

The Mre11 enzyme plays a central role in essential cellular processes such as DNA repair and meiosis, where its endonuclease and exonuclease activities are critical for maintaining genomic stability. Previous studies have linked Mre11 to cell cycle regulation and cancer progression; however, knowledge about DNA processing mechanisms in medically relevant protozoan parasites remains limited. Toxoplasma gondii harbours several essential genes, involved in the DNA damage response, including mre11. The aim of this study was to characterize T. gondii Mre11 (TgMre11) at the molecular level as a potential therapeutic target. Our results demonstrate that TgMre11 core contains an extended eukaryotic insertion loop that modulates its endonuclease activity, resulting in higher levels compared to its human homologue. This feature likely reflects an adaptation to the parasite´s rapid replication rate during the tachyzoite stage. Additionally, structural and mechanistic similarities with prokaryotic homologues were identified, providing insights into the absence of certain DNA repair partners typically associated with Mre11 in T. gondii. Overall, our findings highlight TgMre11 as a promising candidate for the development of selective inhibitors against pathogenic parasites.