Suppression by RNA Polymerase I Inhibitors Varies Greatly Between Distinct RNA Polymerase I Transcribed Genes in Malaria Parasites.

Abstract

The transcription of ribosomal RNA (rRNA) by RNA Polymerase I (Pol I) is the rate-limiting step in ribosome biogenesis and a major determinant of cellular growth rates. Unlike other eukaryotes, which express identical rRNA from large tandem arrays of dozens to hundreds of identical rRNA genes in every cell, the genome of the human malaria parasite Plasmodium falciparum contains only a handful single-copy 47S rRNA loci that differ substantially from one another in length, sequence, and expression in different cell types. We found that the growth of the malaria parasite was acutely sensitive to the Pol I inhibitors 9-hydroxyellipticine and BMH-21 and demonstrated that they greatly reduce the transcription of 47S rRNAs as well as the transcription of other non-coding RNA genes. This makes P. falciparum only the second known organism where RNA Polymerase I transcribes genes other than the 47S rRNAs. We found that the various types of Pol I-transcribed genes differed by more than two orders of magnitude in their susceptibility to these inhibitors and explored the implications of these findings for the regulation of rRNA in P. falciparum.