TY - JOUR
T1 - The 3M Complex Maintains Microtubule and Genome Integrity
AU - Yan, Jun
AU - Yan, Feng
AU - Li, Zhijun
AU - Sinnott, Becky
AU - Cappell, Kathryn M.
AU - Yu, Yanbao
AU - Mo, Jinyao
AU - Duncan, Joseph A.
AU - Chen, Xian
AU - Cormier-Daire, Valerie
AU - Whitehurst, Angelique W.
AU - Xiong, Yue
N1 - Funding Information:
We are grateful to Ted Salmon, Jim Bear, and Steve Rogers for the insightful discussions and assistance throughout this study and to Sarah Jackson and Jordan Kardos for critically reading the manuscript. J.A.D. was supported by the Burroughs Wellcome Fund Career Award for Medical Scientists. This study was supported by NIH grants 1U24CA160035 from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC) to X.C., CA154699 to A.W.W., and CA068377 to Y.X.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2014.03.047
DO - 10.1016/j.molcel.2014.03.047
M3 - Article
C2 - 24793695
AN - SCOPUS:84901836016
SN - 1097-2765
VL - 54
SP - 791
EP - 804
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -