Investigating ubiquitination-regulated cell cycle events underpinning malaria transmission

Genome replication is fundamental to proliferation of all living cells. Although the core DNA replication machinery is conserved across higher eukaryotes, cell cycle events in evolutionarily divergent organisms, such as Plasmodium (the malaria parasite), are regulated by unusual replication and chromatin dynamics. Plasmodium proliferates using mitosis in the vertebrate host, while both mitotic and meiotic genome replication are crucial for transmission stages in the mosquito. During transmission, sexual precursor cells or male gametocytes can achieve incredible speeds of DNA replication to complete three rounds of genome replication within just 10 minutes to generate motile gametes that fertilize female cells to form zygotes. Zygotes undergo meiotic replication that can take up to three hours. Although several signalling pathways regulated by phosphorylation have been identified to regulate DNA replication, we still know little about how the parasite prepares the DNA and chromatin architecture prior to duplication of the genome. It was recently discovered that an eraser of ubiquitin marks, the deubiquitinase USP7 (ubiquitin specific protease 7), to be a central regulator for initiating DNA replication in both mitosis and meiosis. This is particularly exciting because removal of USP7 completely blocks parasite transmission and deubiquitinase enzymes are very tractable to inhibition by small pharmaceuticals. Understanding the interplay between USP7 and the signalling networks that regulate mitosis and meiosis will reveal new targets and strategies for transmission blocking.

Project details

Basic Science

Mar 2024 — Feb 2027

$822,375

United Kingdom