Malaria parasites possess a telomere repeat-binding protein that shares ancestry with transcription factor IIIA

Abstract

Telomere repeat-binding factors (TRFs) are essential components of the molecular machinery that regulates telomere function. TRFs are widely conserved across eukaryotes and bind duplex telomere repeats via a characteristic MYB-type domain. Here, we identified the telomere repeat-binding protein PfTRZ in the malaria parasite Plasmodium falciparum, a member of the Alveolate phylum for which TRFs have not been described so far. PfTRZ lacks an MYB domain and binds telomere repeats via a CH-type zinc finger domain instead. In vivo, PfTRZ binds with high specificity to the telomeric tract and to interstitial telomere repeats upstream of subtelomeric virulence genes. Conditional depletion experiments revealed that PfTRZ regulates telomere length homeostasis and is required for efficient cell cycle progression. Intriguingly, we found that PfTRZ also binds to and regulates the expression of 5S rDNA genes. Combined with detailed phylogenetic analyses, our findings identified PfTRZ as a remote functional homologue of the basic transcription factor TFIIIA, which acquired a new function in telomere maintenance early in the apicomplexan lineage. Our work sheds unexpected new light on the evolution of telomere repeat-binding proteins and paves the way for dissecting the presumably divergent mechanisms regulating telomere functionality in one of the most deadly human pathogens.

Chromatin Accessibility-Based Characterization of the Gene Regulatory Network Underlying Plasmodium falciparum Blood-Stage Development

“…Therefore, to our surprise, besides AP2s, we did not consistently detect any other protein family in our DNA pull-downs that could function as a sequence-specific DNA-binding factor. Hence, despite the existence of few other types of DNA-binding factors in Plasmodium (including C2H2-type [ Bertschi et al., 2017 ], Myb-type [ Gissot et al., 2005 ], and HMGB-domain proteins [ Briquet et al., 2006 ]), so far all evidence suggests that the ApiAP2 family can be regarded as the major TF family in Plasmodium , leaving researchers puzzled as to how such a small number of factors can govern such a delicate gene expression program. Combinatorial action of multiple TFs has been suggested to increase the regulatory potential of these factors in directing development of malaria parasites (e.g., Russell et al., 2015 , van Noort and Huynen, 2006 ).…”

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets

“…We found no evidence that quarfloxin kills parasites by inducing telomere dysfunction, despite the predominance of PQSs in telomere repeats, since telomere maintenance appeared to be normal after up to 15 cycles of growth in quarfloxin. This does not conclusively exclude the possibility of an acutely lethal telomere dysfunction being induced at higher drug exposures, but the tools to assess this in P. falciparum are lacking: the parasite lacks the variant histone ␥H2AX (35), which is commonly used to detect DNA damage foci, and also lacks all components of the conventional telomere shelterin complex (36).…”

Chromosome End Repair and Genome Stability in Plasmodium falciparum

“…Proteins known to play important roles in telomerase function and telomere stabilization in other organisms, such as TRF, Cdc13, Rad 52, and POT1, could not be identified in the P. falciparum genome using standard bioinformatics approaches, and thus the recruitment, retention, and function of telomerase in P. falciparum is likely to have unique elements, such as the recently characterized protein PfTRZ. This protein was found to be a functional homologue to the transcription factor TFIIIA, yet it is associated with parasite telomeres and has a role in telomere maintenance ( 41 ).…”