REVEALING HOW THE UBIQUITINATION CYCLE CONTRIBUTES TO GENOME MAINTENANCE IN LEISHMANIA

Cycles of ubiquitination and deubiquitination, the addition and removal of a 76 amino acid polypeptide to lysine residues of target proteins, play a key cellular role in controlling the turnover, localisation and activity of many proteins, thereby modulating many cellular reactions. Two such ubiquitin-regulated reactions are DNA repair and replication, which together maintain

and transmit all genomes. Nothing is known about how ubiquitination acts during Leishmania DNA repair or replication, but this grouping of single-celled eukaryotic parasites displays remarkable genome plasticity, manifest as both changes in gene and chromosome copy number. This project will ask if and how ubiquitination regulates the DNA repair and replication

machineries of Leishmania, including how such modifications contribute to genome plasticity. In so doing, the project will provide new knowledge on the regulation of known genome maintenance machineries and will identify novel activities. In the long run, such knowledge provides the potential to develop improved and novel anti-Leishmania compounds targeting the

ubiquitination system. The project will involve training in cell culture and genetic manipulation, as well as in the generation and analysis of large-scale next generation DNA sequencing and proteomics datasets.