title: CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity.
abstract: The Cullin 9 (CUL9) gene encodes a putative E3 ligase that localizes in the cytoplasm. Cul9 null mice develop spontaneous tumors in multiple organs; however, both the cellular and the molecular mechanisms of CUL9 in tumor suppression are currently unknown. We show here that deletion of Cul9 leads to abnormal nuclear morphology, increased DNA damage, and aneuploidy. CUL9 knockdown rescues the microtubule and mitosis defects in cells depleted for CUL7 or OBSL1, two genes that are mutated in a mutually exclusive manner in 3M growth retardation syndrome and function in microtubule dynamics. CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7. Depletion of CUL7 decreases survivin level, and overexpression of survivin rescues the defects caused by CUL7 depletion. We propose a 3M-CUL9-survivin pathway in maintaining microtubule and genome integrity, normal development, and tumor suppression.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Cappell
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA; Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. Electronic address: yxiong@email.unc.edu.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016923:Cell Death; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D045325:HCT116 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology; D011123:Polyploidy; D055503:Protein Multimerization; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin; D054875:Ubiquitination
chemical_list: C117749:Birc5 protein, mouse; C000590013:CUL9 protein, mouse; C494817:Cul7 protein, mouse; D044842:Cullin Proteins; D051034:Inhibitor of Apoptosis Proteins; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D000077022:Survivin