3′‐end mRNA processing within apicomplexan parasites, a patchwork of classic, and unexpected players

Abstract

The 3′‐end processing of mRNA is a co‐transcriptional process that leads to the formation of a poly‐adenosine tail on the mRNA and directly controls termination of the RNA polymerase II juggernaut. This process involves a megadalton complex composed of cleavage and polyadenylation specificity factors (CPSFs) that are able to recognize cis‐sequence elements on nascent mRNA to then carry out cleavage and polyadenylation reactions. Recent structural and biochemical studies have defined the roles played by different subunits of the complex and provided a comprehensive mechanistic understanding of this machinery in yeast or metazoans. More recently, the discovery of small molecule inhibitors of CPSF function in Apicomplexa has stimulated interest in studying the specificities of this ancient eukaryotic machinery in these organisms. Although its function is conserved in Apicomplexa, the CPSF complex integrates a novel reader of the N6‐methyladenosine (m6A). This feature, inherited from the plant kingdom, bridges m6A metabolism directly to 3′‐end processing and by extension, to transcription termination. In this review, we will examine convergence and divergence of CPSF within the apicomplexan parasites and explore the potential of small molecule inhibition of this machinery within these organisms.This article is categorized under: RNA Processing > 3′ End Processing RNA Processing > RNA Editing and Modification

Targeted protein degradation of the CPSF complex by benzoxaboroles through sumoylation

“…A common target, cleavage and polyadenylation specificity factor 3 (CPSF73/CPSF3/YSH1) has been identified for BoB activity against multiple protists (Sonoiki et al, 2017, Palencia et al, 2017, Wall et al, 2018, Mowbray et al, 2021). CPSF3 is widely conserved, with endonuclease activity recognising the pre-mRNA 3’-cleavage site AAUAAA prior to polyadenylation (reviewed in Swale and Hakimi, 2023). Amongst many identified functions, CPSF3 also possesses 5’ to 3’ exonuclease activity and operates in a U7 snRNP-dependent manner.…”

“…CPSF3 is the sole catalytic component of the CPSF complex and the target of several distinct BoBs in multiple unicellular protozoan parasites, including Plasmodium falciparum, Toxoplasma gondii, Trypanosoma brucei and T. cruzi (reviewed in Swale and Hakimi 2023, Has et al, 2023). Evidence that CPSF3 represents the trypanosome target is supported by demonstrations that trans -splicing is inhibited by multiple BoBs (Begolo et al, 2018, Waithaka and Clayton 2022) and from overexpression screens and drug resistance-associated mutation at the drug-binding site (Wall et al, 2018).…”