Sororin pre-mRNA splicing is required for proper sister chromatid cohesion in human cells

Sister chromatid cohesion, which depends on cohesin, is essential for the faithful segregation of replicated chromosomes. Here, we report that splicing complex Prp19 is essential for cohesion in both G2 and mitosis, and consequently for the proper progression of the cell through mitosis. Inactivation of splicing factors SF3a120 and U2AF65 induces similar cohesion defects to Prp19 complex inactivation. Our data indicate that these splicing factors are all required for the accumulation of cohesion factor Sororin, by facilitating the proper splicing of its pre‐mRNA. Finally, we show that ectopic expression of Sororin corrects defective cohesion caused by Prp19 complex inactivation. We propose that the Prp19 complex and the splicing machinery contribute to the establishment of cohesion by promoting Sororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability. Synopsis Sororin expression is shown to be critically sensitive to perturbations of the splicing machinery, which therefore result in defects in sister chromatid cohesion and genome instability. The Prp19 complex is required for sister chromatid cohesion and progression through mitosis The Prp19 complex enables Sororin protein accumulation through splicing of its pre‐mRNA The splicing factors U2AF65 and SF3a120 are also essential for cohesion and Sororin accumulation Correction of Sororin level rescues cohesion defects caused by Prp19 complex inactivation Graphical Abstract Sororin expression is shown to be critically sensitive to perturbations of the splicing machinery, which therefore result in defects in sister chromatid cohesion and genome instability.