The 3M Complex Maintains Microtubule and Genome Integrity

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...

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Published in:Molecular cell 2014-06, Vol.54 (5), p.791-804
Main Authors: Yan, Jun, Yan, Feng, Li, Zhijun, Sinnott, Becky, Cappell, Kathryn M., Yu, Yanbao, Mo, Jinyao, Duncan, Joseph A., Chen, Xian, Cormier-Daire, Valerie, Whitehurst, Angelique W., Xiong, Yue
Format: Article
Language:English
Subjects:
Carrier Proteins - metabolism
Cell Line, Tumor
Centrosome - metabolism
Cullin Proteins - genetics
Cullin Proteins - metabolism
Cytoskeletal Proteins - metabolism
Dwarfism - genetics
F-Box Proteins - metabolism
Genome, Human
Genomic Instability
HEK293 Cells
Humans
Microtubules - metabolism
Muscle Hypotonia - genetics
Mutation, Missense
Protein Transport
Spindle Apparatus - metabolism
Spine - abnormalities
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Summary: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. [Display omitted] •A mammalian-specific complex regulating microtubule and cell division•A mechanism for 3M syndrome and related development disorders•CCDC8 maintains centrosomal localization of CUL7 and is reduced by microtubule damage CUL7, OBSL1, and CCDC8 genes are mutated in a mutually exclusive manner in 3M and other growth retardation syndromes. Yan et al. demonstrate that the products of three 3M genes form a functional complex (the 3M complex) to regulate microtubule dynamics and cell division.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2014.03.047