title: The 3M complex maintains microtubule and genome integrity.
abstract: CUL7, OBSL1, and CCDC8 genes are mutated in a mutually exclusive manner in 3M and other growth retardation syndromes. The mechanism underlying the function of the three 3M genes in development is not known. We found that OBSL1 and CCDC8 form a complex with CUL7 and regulate the level and centrosomal localization of CUL7, respectively. CUL7 depletion results in altered microtubule dynamics, prometaphase arrest, tetraploidy, and mitotic cell death. These defects are recaptured in CUL7 mutated 3M cells and can be rescued by wild-type, but not by 3M patient-derived CUL7 mutants. Depletion of either OBSL1 or CCDC8 results in defects and sensitizes cells to microtubule damage similarly to loss of CUL7 function. Microtubule damage reduces the level of CCDC8 that is required for the centrosomal localization of CUL7. We propose that CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development.
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: 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: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Becky
authors.initials: B
authors.lastname: Sinnott
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 Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Yanbao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Mo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants-Malades, 75015 Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
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: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism; D015894:Genome, Human; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D009123:Muscle Hypotonia / Q000235:genetics; D020125:Mutation, Missense; D021381:Protein Transport; D008941:Spindle Apparatus / Q000378:metabolism; D013131:Spine / Q000002:abnormalities
chemical_list: C569196:CCDC8 protein, human; C506299:CUL7 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; C526069:FBXW8 protein, human; C522000:OBSL1 protein, human