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.

Bioinformatics Centre Biotech Research and Innovation Centre University of Copenhagen Copenhagen Denmark

Department of Cell Death and Metabolism Danish Cancer Society Research Center Copenhagen Denmark

Department of Proteomics The Novo Nordisk Foundation Center for Protein Research University of Copenhagen Copenhagen Denmark

Department of Proteomics The Novo Nordisk Foundation Center for Protein Research University of Copenhagen Copenhagen Denmark Institute of Molecular Biology Mainz Germany

Institute of Molecular and Translational Medicine Palacky University Olomouc Czech Republic

Ubiquitin Signaling Group Department of Disease Biology The Novo Nordisk Foundation Center for Protein Research University of Copenhagen Copenhagen Denmark

EMBO J. 2014 Nov 18;33(22):2601-3. doi: 10.15252/embj.201489988. PubMed

Zobrazit více v PubMed

van der Veen AG, Ploegh HL. Ubiquitin-like proteins. Annu Rev Biochem. 2012;81:323–357. PubMed

Hochstrasser M. Origin and function of ubiquitin-like proteins. Nature. 2009;458:422–429. PubMed PMC

McNally T, Huang Q, Janis RS, Liu Z, Olejniczak ET, Reilly RM. Structural analysis of UBL5, a novel ubiquitin-like modifier. Protein Sci. 2003;12:1562–1566. PubMed PMC

Ramelot TA, Cort JR, Yee AA, Semesi A, Edwards AM, Arrowsmith CH, Kennedy MA. Solution structure of the yeast ubiquitin-like modifier protein Hub1. J Struct Funct Genomics. 2003;4:25–30. PubMed

Wilkinson CR, Dittmar GA, Ohi MD, Uetz P, Jones N, Finley D. Ubiquitin-like protein Hub1 is required for pre-mRNA splicing and localization of an essential splicing factor in fission yeast. Curr Biol. 2004;14:2283–2288. PubMed

Yashiroda H, Tanaka K. Hub1 is an essential ubiquitin-like protein without functioning as a typical modifier in fission yeast. Genes Cells. 2004;9:1189–1197. PubMed

Mishra SK, Ammon T, Popowicz GM, Krajewski M, Nagel RJ, Ares M, Jr, Holak TA, Jentsch S. Role of the ubiquitin-like protein Hub1 in splice-site usage and alternative splicing. Nature. 2011;474:173–178. PubMed PMC

Nasmyth K, Haering CH. Cohesin: its roles and mechanisms. Annu Rev Genet. 2009;43:525–558. PubMed

Peters JM, Nishiyama T. Sister chromatid cohesion. Cold Spring Harb Perspect Biol. 2012;4:a011130. PubMed PMC

Rankin S, Ayad NG, Kirschner MW. Sororin, a substrate of the anaphase-promoting complex, is required for sister chromatid cohesion in vertebrates. Mol Cell. 2005;18:185–200. PubMed

Lafont AL, Song J, Rankin S. Sororin cooperates with the acetyltransferase Eco2 to ensure DNA replication-dependent sister chromatid cohesion. Proc Natl Acad Sci USA. 2010;107:20364–20369. PubMed PMC

Nishiyama T, Ladurner R, Schmitz J, Kreidl E, Schleiffer A, Bhaskara V, Bando M, Shirahige K, Hyman AA, Mechtler K, et al. Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell. 2010;143:737–749. PubMed

Kueng S, Hegemann B, Peters BH, Lipp JJ, Schleiffer A, Mechtler K, Peters JM. Wapl controls the dynamic association of cohesin with chromatin. Cell. 2006;127:955–967. PubMed

Hauf S, Roitinger E, Koch B, Dittrich CM, Mechtler K, Peters JM. Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2. PLoS Biol. 2005;3:e69. PubMed PMC

Liu H, Rankin S, Yu H. Phosphorylation-enabled binding of SGO1-PP2A to cohesin protects sororin and centromeric cohesion during mitosis. Nat Cell Biol. 2013;15:40–49. PubMed PMC

Lara-Gonzalez P, Westhorpe FG, Taylor SS. The spindle assembly checkpoint. Curr Biol. 2012;22:R966–R980. PubMed

Salic A, Waters JC, Mitchison TJ. Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis. Cell. 2004;118:567–578. PubMed

Ong SE, Foster LJ, Mann M. Mass spectrometric-based approaches in quantitative proteomics. Methods. 2003;29:124–130. PubMed

Vitting-Seerup K, Porse BT, Sandelin A, Waage J. spliceR: an R package for classification of alternative splicing and prediction of coding potential from RNA-seq data. BMC Bioinformatics. 2014;15:81. PubMed PMC

Popp MW, Maquat LE. Organizing principles of Mammalian nonsense-mediated mRNA decay. Annu Rev Genet. 2013;47:139–165. PubMed PMC

Wong JJ, Ritchie W, Ebner OA, Selbach M, Wong JW, Huang Y, Gao D, Pinello N, Gonzalez M, Baidya K, et al. Orchestrated intron retention regulates normal granulocyte differentiation. Cell. 2013;154:583–595. PubMed

Neumann B, Walter T, Hériché JK, Bulkescher J, Erfle H, Conrad C, Rogers P, Poser I, Held M, Liebel U, et al. Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes. Nature. 2010;464:721–727. PubMed PMC

Hutchins JR, Toyoda Y, Hegemann B, Poser I, Hériché JK, Sykora MM, Augsburg M, Hudecz O, Buschhorn BA, Bulkescher J, et al. Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science. 2010;328:593–599. PubMed PMC

Poulsen M, Lukas C, Lukas J, Bekker-Jensen S, Mailand N. Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks. J Cell Biol. 2012;197:189–199. PubMed PMC

Poulsen SL, Hansen RK, Wagner SA, van Cuijk L, van Belle GJ, Streicher W, Wikström M, Choudhary C, Houtsmuller AB, Marteijn JA, et al. RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. J Cell Biol. 2013;201:797–807. PubMed PMC