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.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• chromatidy genetika   MeSH
• HeLa buňky MeSH
• lidé MeSH
• ligasy genetika   MeSH
• mitóza genetika   MeSH
• oční proteiny genetika   metabolismus   MeSH
• prekurzory RNA genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• regulace genové exprese MeSH
• Saccharomyces cerevisiae - proteiny genetika   MeSH
• segregace chromozomů genetika   MeSH
• sestřih RNA genetika   MeSH
• spliceozomy genetika   MeSH
• ubikvitiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

To elucidate the regulator-versus-target relationship in the cyclin D1/cdk4/retinoblastoma protein (pRB) pathway, we examined fibroblasts from RB-1 gene-deficient and RB-1 wild-type littermate mouse embryos (ME) and in human tumor cell lines that differed in the status of the RB-1 gene. The RB+/+ and RB-/- ME fibroblasts expressed similar protein levels of D-type cyclins, cdk4, and cdk6, showed analogous spectra and abundance of cellular proteins complexed with cdk4 and/or cyclins D1 and D2, and exhibited comparable associated kinase activities. Of the two human cell lines established from the same sarcoma biopsy, the RB-positive SKUT1B cells contained cdk4 that was mainly associated with D-type cyclins, contrary to a predominant cdk4-p16INK4 complex in the RB-deficient SKUT1A cells. Antibody-mediated neutralization of cyclin D1 arrested the RB-positive ME and SKUT1B cells in G1, whereas this cyclin appeared dispensable in the RB-deficient ME and SKUT1A cells. Lack of requirement for cyclin D1 therefore correlated with absence of functional pRB, regardless of whether active cyclin D1/cdk4 holoenzyme was present in the cells under study. Consistent with a potential role of cyclin D/cdk4 in phosphorylation of pRB, monoclonal anti-cyclin D1 antibodies supporting the associated kinase activity failed to significantly affect proliferation of RB-positive cells, whereas the antibody DCS-6, unable to coprecipitate cdk4, efficiently inhibited G1 progression and prevented pRB phosphorylation in vivo. These data provide evidence for an upstream control function of cyclin D1/cdk4, and a downstream role for pRB, in the order of events regulating transition through late G1 phase of the mammalian cell division cycle.

• MeSH
• cyklin D1 MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasy * MeSH
• cykliny antagonisté a inhibitory   imunologie   metabolismus   MeSH
• DNA primery genetika   MeSH
• fosforylace MeSH
• G1 fáze * fyziologie   genetika   MeSH
• geny retinoblastomu * MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• neutralizační testy MeSH
• onkogenní proteiny antagonisté a inhibitory   imunologie   metabolismus   MeSH
• protein-serin-threoninkinasy * metabolismus   MeSH
• protoonkogenní proteiny * MeSH
• retinoblastomový protein genetika   metabolismus   MeSH
• sekvence nukleotidů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH