The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing 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.

XAP5 CIRCADIAN TIMEKEEPERregulates RNA splicing and the circadian clock via genetically separable pathways

“…Yet another possibility is that XCT affects a cellular process independently of its role in gene expression. For example, PRP19 is known to facilitate DNA repair by its E3 ubiquitin ligase activity independent of its involvement in the spliceosomal complex (Maréchal et al, 2014; Idrissou and Maréchal, 2022). Indeed, there is increasing evidence that many RNA binding proteins directly participate in DNA double-strand break responses (Klaric et al, 2021).…”

The Prp19C subunit Syf2 and the Prp19C-associated protein Cwc15 function in TREX occupancy and transcription elongation

“…Prp19C stabilizes the association of the U5 and U6 snRNPs by promoting RNA–RNA interaction between U5 and U6 in the activated spliceosomal B* complex, which catalyzes the first transesterification reaction and remains bound throughout the second step of splicing ( Tarn et al 1994 ; Chan et al 2003 ; Chan and Cheng 2005 ; Fabrizio et al 2009 ). In addition to splicing and transcription elongation, Prp19C is involved in genome stability ( Idrissou and Maréchal 2022 ) and lipid droplet formation ( Cho et al 2007 ). Like the TREX complex, Prp19C is conserved from yeast to human.…”

Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo

“…Mammals only have seven U-box ligases, of which carboxy-terminus of HSC70 interacting protein (CHIP), pre-mRNA processing factor 19 (PRP19) and ubiquitin conjugation factor E4B (Ube4B) have been partially characterized. These ligases regulate protein quality control, DNA repair and apoptosis [ [14] , [15] , [16] , [17] ]. Moreover, neuron-specific expression of Ube4B has been shown to augment obesity and hepatic steatosis in mice [ 18 ].…”