The SCF^Slimb ubiquitin ligase directly targets condensin II for degradation and functions to modulate 3D interphase chromosome spatial organization. Giovanni Bosco¹, Daniel W. Buster², Scott G. Daniel², Huy Q. Nguyen¹, Sarah L. Windler³, Maureen Peterson¹, Meredith Roberts², Joy H. Meserve², Tom Hartl², Joey E. Klebba², David Builder³, Gregory C. Rogers². 1) Genetics & Norris Cotton Cancer Ctr, Geisel Sch Med at Dartmouth, Hanover, NH; 2) Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; 3) Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

   The SCF^Slimb E3 ubiquitin ligase has been previously shown to localize to the nucleus, but the role it may play in modulating chromosome structure and spatial organization is not well understood. We show that RNAi depletion of Slimb in cultured cells as well as slimb mutations in vivo lead to dramatic global changes in interphase chromosome morphology. Upon depletion of Slimb chromosomes become hypercondensed, homologs unpair and we observe defects in nuclear envelope morphology. These phenotypes are also seen in Cul-1 and SkpA RNAi, confirming that all three SCF subunits contribute to these phenotypes. Slimb RNAi in vivo and loss-of-function mutations in nurse cells as well as diploid larval tissues recapitulate all these phenotypes. Interestingly, we find that all these phenotypes are due to a failure to degrade the Cap-H2 condensin II subunit, and we show that the SCF^Slimb E3 ligase normally targets Cap-H2 for ubiquitination and protein degradation. Moreover, chromatin fractionation experiments reveal that Slimb itself is chromatin bound, raising the possibility that condensin II activity on chromatin may be regulated by selective ubiquitination and removal of Cap-H2. We propose a model where chromatin-tethered SCF^Slimb regulation of Cap-H2 protein levels is critical for maintenance of chromosome organization in interphase.