UBL5 is essential for pre-mRNA splicing and sister chromatid cohesion in human cells

UBL5 is an atypical ubiquitin‐like protein, whose function in metazoans remains largely unexplored. We show that UBL5 is required for sister chromatid cohesion maintenance in human cells. UBL5 primarily associates with spliceosomal proteins, and UBL5 depletion decreases pre‐mRNA splicing efficiency, leading to globally enhanced intron retention. Defective sister chromatid cohesion is a general consequence of dysfunctional pre‐mRNA splicing, resulting from the selective downregulation of the cohesion protection factor Sororin. As the UBL5 yeast orthologue, Hub1, also promotes spliceosome functions, our results show that UBL5 plays an evolutionary conserved role in pre‐mRNA splicing, the integrity of which is essential for the fidelity of chromosome segregation. Synopsis The ubiquitin‐like protein UBL5 is shown to be required for pre‐mRNA splicing. Its absence leads to aberrant Sororin mRNA intron retention, low Sororin protein levels, and thus defective sister chromatid cohesion in human cells. UBL5 is essential for sister chromatid cohesion maintenance in human cells. Quantitative mass spectrometry analysis shows that UBL5 is mainly associated with spliceosomal proteins. Loss of UBL5 blocks pre‐mRNA splicing, leading to intron retention. Knockdown of UBL5 or other splicing factors leads to missplicing of Sororin transcripts and, thus, a decrease in Sororin protein levels that causes premature sister chromatid separation. Graphical Abstract The ubiquitin‐like protein UBL5 is shown to be required for pre‐mRNA splicing. Its absence leads to aberrant Sororin mRNA intron retention, low Sororin protein levels, and thus defective sister chromatid cohesion.