The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability

SIMPLE SUMMARY: mRNA maturation is absolutely required for proper gene expression and, in recent years, regulators of this process have been found to be tightly intertwined with genome stability. The E3 ubiquitin ligase PRP19 is part of multiple protein complexes that regulate mRNA splicing, RNA:DNA hybrid resolution, activation of the ATR-mediated DNA damage response, DNA repair and cell division. Here, we discuss how this essential evolutionarily conserved factor functions at the nexus between mRNA processing and genome protection and we highlight key questions that will need to be addressed to better understand the interface between gene expression and genome stability. ABSTRACT: mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.