Cathepsin C-like protease regulates DNA replication by histone H3 N-terminal clipping in malaria parasites. Plasmodium histone H3 clipping

Post-translational modifications (PTMs) of histone N-terminal tails are key regulators of gene expression in the human malaria parasite Plasmodium falciparum. Here, we identify developmentally controlled proteolytic clipping of the N-terminus of histone H3 at amino acid position 21 by a cathepsin C-type protease termed dipeptidyl aminopeptidase 2 (PfDPAP2) as a new PTM in intra-erythrocytic parasite stages. Conditionally knocked down PfDPAP2 abrogated histone H3 clipping and blocked intra-erythrocytic parasite DNA replication. Correspondingly, genome-wide occupancy of clipped histone H3 identified the upstream regions of several DNA replication genes as targets of the protease. Because episomally expressed clipped histone H3 showed nucleosomal incorporation at similar genomic loci as the endogenous clipped protein, this points to a novel type of nucleosome replacement mechanism in P. falciparum. The discovery of an unprecedented protease-mediated, epigenetic control mechanism of DNA replication makes PfDPAP2 a promising therapeutic target to develop anti-malarials.