Does kinase ATM participate in genome plasticity modulation in Leishmania?

• Grant number: 25/09797-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Luiz Ricardo Orsini Tosi
• Grantee: Raul Alexander Gonzáles Córdova
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/03015-0 - Of epigenetics, genomic variability and gene expression regulation in Leishmania, AP.TEM

Abstract

Leishmania adaptability to different environmental conditions is often correlated to genome plasticity and general chromosome and gene copy number variations (Black et al.,2023). The mechanisms by which DNA Replication Stress modulates genome plasticity in Leishmania are complex and involve multiple DNA Damage Repair pathways. Understanding these mechanisms will provide valuable insights into the biology of Leishmania and may lead to the development of new strategies for the control of this important human pathogen. The ataxia telangectasia and Rad3-related (ATR) checkpoint kinase is a central kinase in the response to replication stress and participates in cell cycle arrest signaling, in the regulation of replication origin firing, and in the replication fork stability and restart. Hence, ATR is a key determinant of genome stability and variability. One pivotal finding in our study of Leishmania ATR was that ATR depletion leads to increased DNA damage, as measured by the accumulation of double-strand breaks and the abrogation of a S-G2/M checkpoint. This finding indicated functional overlap with another central kinase, the Ataxia Telangectasia mutated kinase (ATM) (Lee & Paull, 2021) and prompt us to ask if ATM would participate in Leishmania genome stability and plasticity. We already know that Leishmania ATM is non-essential though its loss significantly sensitizes cells to genotoxins and abrogates a specific histone H2A phosphorylation, which is a marker of DNA damage in trypanosomatids (¿H2A). Thus, ATM plays a role in the Leishmania DDR and could participate in genome maintenance and plasticity. Thus, we plan to characterize the Leishmania ATM kinase which, in other eukaryotes, is at the pinnacle of the DDR being the primary responder to double-strand DNA breaks. Our main goal is to explore ATM participation in genome variability. (AU)