A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology

Abstract

The untangling or overwinding of genetic material is an inevitable part of DNA replication, repair, recombination, and transcription. Topoisomerases belong to a conserved enzyme family that amends DNA topology during various processes of DNA metabolism. To relax the genetic material, topoisomerases transiently break the phosphodiester bond on one or both DNA strands and remain associated with the cleavage site by forming a covalent enzyme–DNA intermediate. This releases torsional stress and allows the broken DNA to be re-ligated by the enzyme. The biological function of topoisomerases ranges from the separation of sister chromatids following DNA replication to the aiding of chromosome condensation and segregation during mitosis. Topoisomerases are also actively involved in meiotic recombination. The unicellular apicomplexan parasite, Plasmodium falciparum, harbors different topoisomerase subtypes, some of which have substantially different sequences and functions from their human counterparts. This review highlights the biological function of each identified Plasmodium topoisomerase along with a comparative analysis of their orthologs in human or other model organisms. There is also a focus on recent advancements towards the development of topoisomerase chemical inhibitors, underscoring the druggability of unique topoisomerase subunits that are absent in humans. Plasmodium harbors three distinct genomes in the nucleus, apicoplast, and mitochondria, respectively, and undergoes non-canonical cell division during the schizont stage of development. This review emphasizes the specific developmental stages of Plasmodium on which future topoisomerase research should focus.

Plasmodium Topoisomerase VIB and Spo11 Constitute Functional Type IIB Topoisomerase in Malaria Parasite: Its Possible Role in Mitochondrial DNA Segregation

“…Earlier we found that the two subunits of PfTopoVI were predominantly expressed in the schizont-specific stages compared to the ring and trophozoite stages, respectively ( 9 ). In order to have a better understanding of the function of PfTopoVI, we measured the transcripts of other type II topoisomerase subunits identified in the parasite ( 2 ) at three distinct developmental stages within the schizont. We used tightly synchronized parasites 35 to 36 h postinvasion (hpi) as early schizont (ES) stage-specific, 39 to 40 hpi as mid-schizont (MS) stage-specific, and 44 to 45 hpi as late schizont (LS) stage-specific parasites for all of our experiments ( Fig.…”

“…There is only 10% identity in the amino acid sequences between Plasmodium TopoVIB and human TopoVIBL protein ( 2 ). A multiple-sequence alignment of the Bergerat fold region from different species is shown in Fig.…”

“…This necessitates the importance of basic research with malaria parasites to identify novel proteins that can act as an antimalarial target. Topoisomerases pose an attractive antimalarial target due to the absence of some of the unique topoisomerases from the human genome ( 2 ).…”