The acetylation of histones is accomplished by a unique subset of enzymes known as histone acetyltransferases (HATs). The MYST family (MOZ, Ybf2/Sas3, Sas2, and TIP60) of histone acetyltransferases (HATs) are highly conserved in eukaryotes and are responsible for a considerable fraction of all protein acetylation (Yang, 2004). HATs aid DNA replication by regulating origin activity, licensing, and gene expression (Aggarwal and Calvi, 2004; Doyon et al., 2006; Iizuka et al., 2006). The interaction of HBO1, a MYST family acetyltransferase, with ORC1 suggests that HBO1-mediated chromatin acetylation may be involved in DNA replication and gene expression control (Iizuka and Stillman, 1999).

HBO1 was also shown to interact with replication licensing proteins like MCM2 and ORC1 (Burke et al., 2001). Further, HBO1 histone acetylase coactivates the replication licensing factor Cdt1 (Miotto and Struhl, 2008). Previous research has demonstrated that Geminin inhibits HBO1 histone acetyltransferase activity, which in turn prevents DNA replication (Miotto and Struhl, 2010). Along with Cdt1, HBO1 has also been found to positively govern MCM loading during the G1 phase of the cell cycle by enhancing chromatin accessibility (Wong et al., 2010). It has been shown recently that BRPF3 and HBO1 work together to selectively acetylate histone H3K14. A genome-wide study reveals significant enrichment of BRPF3, HBO1, and H3K14ac at ORC1-binding sites and replication origins located close to TSSs (Feng et al., 2016).

It has been reported earlier that Mst1 histone acetyltransferase plays important role in the opening of chromatin during DNA replication following acetylation of histone 4 K8 and K12 residues (Ruan et al., 2015). Additionally, in S. pombe, NuA4 histone acetyltransferase has been shown to function in DNA replication and fork repair (Noguchi et al., 2019).

Three MYST family HATs (HAT 1–3) have been found in the protozoan parasite Trypanosoma brucei, and they are involved in growth, DNA replication, and telomeric silencing (Kawahara et al., 2008). MYST has been shown to contribute to the expression of the ATM kinase gene in Toxoplasma gondii in response to DNA damage (Vonlaufen et al., 2010). GCN5 and MYST are two well-studied P. falciparum histone acetyltransferases (Bhowmick et al., 2020; Fan et al., 2004; Miao et al., 2010). A single MYST acetyltransferase has been found and characterized in P. falciparum. Interestingly, two PfMYST forms (full-length and a short version) express from a single gene due to different transcription initiation sites in 5ꞌ UTR of the Pfmyst gene as well as within the coding region (Miao et al., 2010). PfMYST acetylates histone H4 and plays an essential role in cell cycle progression in P. falciparum (Miao et al., 2010). Additionally, PfMYST has been reported to interact with the DNA cleaving enzyme RUVBL3 and colocalize with H3K9me1 in the ring stage, implying a function in gene transcription (Sen et al., 2018).

Another HAT in P. falciparum, PfGCN5 is an essential enzyme that has been shown to acetylate histone 3 leading to the regulation of global gene expression in the parasite (Cui et al., 2007). It has been shown that PfGCN5 undergoes proteolytic processing using a cysteine protease-like enzyme that is crucial for its activity in vivo (Bhowmick et al., 2020). Interestingly, inhibition of PfGCN5 processing affects the binding of the protein at the gene promoters with concomitant reduction of H3K9 acetylation level at these promoters. Overall, PfGCN5 controls several genes involved in diverse biological functions including host cell invasion and reprogramming.

Plasmodium has a multi-stage life cycle that is quite complicated, and the parasite employs its replicating machinery very quickly and efficiently. The schizogony takes 48 h to complete inside RBC, while the parasites require 4–6 h to replicate (Arnot et al., 2011). Plasmodium, like any other eukaryote, encodes for most of the replication machinery proteins like the origin recognition complex (ORC), DNA polymerases, Proliferating Cell Nuclear Antigen (PCNA), Minichromosome Maintenance proteins (MCMs), etc. (Ansari and Tuteja, 2012; Deshmukh et al., 2012; Gupta et al., 2008; Kilbey et al., 1993; Mitra et al., 2015; Patterson et al., 2006; Sharma et al., 2018; White and Kilbey, 1996). The role of HATs in DNA replication origin activation in Plasmodium is unknown, owing to the lack of well-defined origins. However, we have recently identified putative Autonomously Replicating Sequences (ARS)-like sequences in the Plasmodium genome (Agarwal et al., 2017). In P. falciparum, we validated some of these ARS-like sequences as potential replication origins.

As discussed above, HATs promote DNA replication by regulating origin activity, licensing, and gene expression (Aggarwal and Calvi, 2004; Doyon et al., 2006; Iizuka et al., 2006). Although PfHATs like PfMYST and PfGCN5 control a diverse set of genes, it remains elusive whether there is any preference for a particular PfHAT for modulating the origin function. In general, Plasmodium has a relatively less number of PfHATs and histone deacetylases (HDAC) compared to other eukaryotes. Here we show that two PfMYST isoforms are distinctly located in different cellular compartments. While the full-length form is found predominantly in the cytoplasm, the shorter form is mostly nuclear. Further, PfMYST but not PfGCN5 is enriched highly in the vicinity of PfARS-like sequences in a cell cycle-specific manner suggesting PfMYST's preferential role in parasite DNA replication.