title: Centromere binding and a conserved role in chromosome stability for SUMO-dependent ubiquitin ligases.
abstract: The Saccharomyces cerevisiae Slx5/8 complex is the founding member of a recently defined class of SUMO-targeted ubiquitin ligases (STUbLs). Slx5/8 has been implicated in genome stability and transcription, but the precise contribution is unclear. To characterise Slx5/8 function, we determined genome-wide changes in gene expression upon loss of either subunit. The majority of mRNA changes are part of a general stress response, also exhibited by mutants of other genome integrity pathways and therefore indicative of an indirect effect on transcription. Genome-wide binding analysis reveals a uniquely centromeric location for Slx5. Detailed phenotype analyses of slx5Δ and slx8Δ mutants show severe mitotic defects that include aneuploidy, spindle mispositioning, fish hooks and aberrant spindle kinetics. This is associated with accumulation of the PP2A regulatory subunit Rts1 at centromeres prior to entry into anaphase. Knockdown of the human STUbL orthologue RNF4 also results in chromosome segregation errors due to chromosome bridges. The study shows that STUbLs have a conserved role in maintenance of chromosome stability and links SUMO-dependent ubiquitination to a centromere-specific function during mitosis.
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Loes A L
authors.initials: LA
authors.lastname: van de Pasch
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Miles
authors.forename: Wilco
authors.initials: W
authors.lastname: Nijenhuis
authors.forename: Nathalie A C H
authors.initials: NA
authors.lastname: Brabers
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.forename: Philip
authors.initials: P
authors.lastname: Lijnzaad
authors.forename: Markus K
authors.initials: MK
authors.lastname: Brown
authors.forename: Jimmy
authors.initials: J
authors.lastname: Ouellet
authors.forename: Yves
authors.initials: Y
authors.lastname: Barral
authors.forename: Geert J P L
authors.initials: GJ
authors.lastname: Kops
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
mesh_terms: D000782:Aneuploidy; D002503:Centromere / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability; D002874:Chromosome Mapping; D017353:Gene Deletion; D016681:Genome, Fungal; D042822:Genomic Instability; D008677:Metaphase; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C515574:Slx8 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D054648:Protein Phosphatase 2; C584366:Rts1 protein, S cerevisiae; C515573:Slx5 protein, S cerevisiae