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bioRxiv · 10.1101/2020.11.06.372391

Phosphorylation of the canonical histone H2A marks foci of damaged DNA in malaria parasite

Goyal, M.·Heinberg, A.·Mitesser, V.·Kandelis-Shalev, S.·Singh, B. K.·Dzikowski, R.
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Abstract

Plasmodium falciparum parasites proliferate within circulating red blood cells and are responsible for the deadliest form of human malaria. These parasites are exposed to numerous intrinsic and external sources that could cause DNA damage, therefore, they have evolved efficient mechanisms to protect their genome integrity and allow them to proliferate in such conditions. In higher eukaryotes, double strand breaks rapidly lead to phosphorylation of the core histone variant H2A.X which marks the site of damaged DNA. We show that in P. falciparum that lacks the H2A.X variant, the canonical PfH2A is phosphorylated on serine 121 upon exposure to sources of DNA damage in a dose dependent manner. We further demonstrate that phosphorylated PfH2A is recruited to foci of damaged chromatin shortly after exposure to sources of damage, while the non-phosphorylated PfH2A remains spread throughout the nucleoplasm. In addition, we found that PfH2A phosphorylation is dynamic and as the parasite repairs its DNA over time, this phosphorylation is removed. We also demonstrate that these phosphorylation dynamics could be used to establish a novel and direct DNA repair assay in P. falciparum. ImportancePlasmodium falciparum is the deadliest human parasite that causes malaria when it reaches the blood stream and begins proliferating inside red blood cells where the parasites are particularly prone to DNA damage. The molecular mechanisms that allow these pathogens to maintain their genome integrity under such condition are also the driving force for acquiring genome plasticity that enable them to create antigenic variation and become resistant to essentially all available drugs. However, mechanisms of DNA damage response and repair have not been extensively studied in these parasites. The paper addresses our recent discovery, that P. falciparum that lacks the histone variant H2A.X, phosphorylates its canonical core histone PfH2A in response to exposure to DNA damage. The process of DNA repair in Plasmodium was mostly studied indirectly. Our findings enabled us to establish a direct DNA repair assay for P. falciparum similar to assays that are widely used in model organisms.

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Goyal, M., Heinberg, A., Mitesser, V., Kandelis-Shalev, S., Singh, B. K., Dzikowski, R.. 2020-11-08. Phosphorylation of the canonical histone H2A marks foci of damaged DNA in malaria parasite. https://doi.org/10.1101/2020.11.06.372391

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