Rtr1 and RPAP2: versatile players in transcription and more

Eukaryotic transcription of mRNAs and some non-coding RNAs is governed by RNA Polymerase II (RNA pol II). The full progression of RNA pol II across a gene - from promoter clearance through transcript elongation and termination - is dependent upon the post-translational modifications (PTMs) of its carboxy-terminal domain (CTD) and the dynamic recruitment of numerous trans-acting factors. Rtr1 in yeast and its human orthologue, RPAP2, have emerged as multifunctional regulators of RNA pol II. Despite evidence supporting their role as Ser5-specific CTD phosphatases, structural and biochemical studies have raised doubts about whether they are bona fide phosphatases or instead function as cofactors that influence the activity of established CTD phosphatases. Furthermore, both proteins have been implicated in processes ranging from RNA pol II biogenesis and nuclear transport to transcriptional elongation and termination. Notably, Rtr1's influence also extends to post-transcriptional events like mRNA stability. In this review, we describe the main functions attributed to Rtr1 and RPAP2, and discuss the role of the human homologue in various diseases.