Uncovering the Role of the ERCC1-XPF Endonuclease in the DNA Repair Mechanism of Plasmodium falciparum

• Grant number: 24/18787-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Carsten Wrenger
• Grantee: Nele Wild
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Genome integrity is continuously challenged by DNA lesions in all organisms. Thus, a functional DNA repair mechanism is essential for cell viability. DNA repair processes include the nucleotide exchange repair (NER), base exchange repair (BER), mismatch repair (MMR), single-strand annealing (SSA), homologous recombination (HR) and non-homologous end-joining (NHEJ). The heterodimeric endonuclease ERCC1-XPF has shown, in humans and in model organisms, to play an important role in DNA repair, being mainly involved in the NER, SSA and HR mechanisms. The complex life cycle of Plasmodium parasites exposes these organisms to constant mutagenic pressure. Therefore, understanding the DNA repair mechanism in the malaria parasites, especially in the most dangerous species, Plasmodium falciparum, is a matter of extreme importance. The absence of information about the long identified ERCC1 XPF orthologs in P. falciparum encouraged us to study their role in the maintenance of genome stability of these parasites. Here, we propose a series of in vitro experiments that would allow for functional and structural characterization of these proteins, uncovering part of the still poorly understood Plasmodium DNA repair mechanism. The findings obtained by our investigation could ultimately contribute to a more complete understanding of how Plasmodium parasites develop drug resistance and could reveal novel targets for antimalarial drug development. (AU)