The SUMO Pathway Is Essential for Nuclear Integrity and Chromosome Segregation in Mice

Abstract

Covalent modification by SUMO regulates a wide range of cellular processes, including transcription, cell cycle, and chromatin dynamics. To address the biological function of the SUMO pathway in mammals, we generated mice deficient for the SUMO E2-conjugating enzyme Ubc9. Ubc9-deficient embryos die at the early postimplantation stage. In culture, Ubc9 mutant blastocysts are viable, but fail to expand after 2 days and show apoptosis of the inner cell mass. Loss of Ubc9 leads to major chromosome condensation and segregation defects. Ubc9-deficient cells also show severe defects in nuclear organization, including nuclear envelope dysmorphy and disruption of nucleoli and PML nuclear bodies. Moreover, RanGAP1 fails to accumulate at the nuclear pore complex in mutant cells that show a collapse in Ran distribution. Together, these findings reveal a major role for Ubc9, and, by implication, for the SUMO pathway, in nuclear architecture and function, chromosome segregation, and embryonic viability in mammals.

Ubc9 Regulates Mitosis and Cell Survival during Zebrafish Development

“…Only recently, Ubc9-deficient mice have been described. However, because of early lethality of mutants shortly after implantation, studies had to be carried out with cultured blastocystes (Nacerddine et al, 2005). Here, we report ubc9 loss-of-function studies in intact zebrafish embryos.…”

“…Knockout studies in mouse have revealed multiple roles of Ubc9 required for proper nuclear function in proliferating cells of the early embryo, such as regulation of overall nuclear organization, chromosome segregation, and nucleocytoplasmic transport (Kuehn, 2005;Nacerddine et al, 2005). In comparison, chondrocyte precursors in ubc9.1 morphants appear to have rather specific defects.…”

“…In vertebrates, the impact of sumoylation on developmental programs is even less clear. Inducible loss of Ubc9 function in a chick cell line leads to polynucleated cells and cell cycle-independent apoptosis (Hayashi et al, 2002), whereas in mouse embryos, loss of Ubc9 causes chromosome mis-segregation and loss of nuclear integrity (Nacerddine et al, 2005). These defects result in early lethality of mutant embryos, preventing analyses to address possible roles of Ubc9 during later developmental processes.…”

Nouvelles fonctions extranucléaires de la sumoylation des protéines dans le système nerveux central

“…Bien que la séquence primaire de SUMO soit différente de celle de l'ubiquitine, la structure tridimensionnelle de ces deux protéines est similaire (Figure 1). La sumoylation est un processus essentiel puisque l'invalidation des enzymes de la sumoylation est délétère pour les cellules eucaryotes [2,3]. Le terme SUMO regroupe une famille de 4 protéines (SUMO1-4), formées chacune d'environ 100 résidus.…”

Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

“…Additionally, sumoylation targets promyelocytic leukemia (PML) and the homeodomain-interacting protein kinase 2 (HIPK2) to specific domains within the nucleus [27]. By knocking out the essential E2 conjugating Ubc9 enzyme, the sumoylation pathway iwas shown to be essential for nuclear integrity and normal segregation of chromosomes [28].…”