Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha.
RanBP2 is a nucleoporin with SUMO E3 ligase activity that functions in both nucleocytoplasmic transport and mitosis. However, the biological relevance of RanBP2 and the in vivo targets of its E3 ligase activity are unknown. Here we show that animals with low amounts of RanBP2 develop severe aneuploidy in the absence of overt transport defects. The main chromosome segregation defect in cells from these mice is anaphase-bridge formation. Topoisomerase IIalpha (Topo IIalpha), which decatenates sister centromeres prior to anaphase onset to prevent bridges, fails to accumulate at inner centromeres when RanBP2 levels are low. We find that RanBP2 sumoylates Topo IIalpha in mitosis and that this modification is required for its proper localization to inner centromeres. Furthermore, mice with low amounts of RanBP2 are highly sensitive to tumor formation. Together, these data identify RanBP2 as a chromosomal instability gene that regulates Topo IIalpha by sumoylation and suppresses tumorigenesis.
Dawlaty
Meelad M
MM
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Malureanu
Liviu
L
Jeganathan
Karthik B
KB
Kao
Esther
E
Sustmann
Claudio
C
Tahk
Samuel
S
Shuai
Ke
K
Grosschedl
Rudolf
R
van Deursen
Jan M
JM
D000705:Anaphase; D000782:Aneuploidy; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002273:Carcinogens; D002503:Centromere / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
D000951:Antigens, Neoplasm; D002273:Carcinogens; D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C094493:ran-binding protein 2; D044767:Ubiquitin-Protein Ligases; D004250:DNA Topoisomerases, Type II