2. Academic Validation
  3. The 3M complex maintains microtubule and genome integrity

The 3M complex maintains microtubule and genome integrity

  • Mol Cell. 2014 Jun 5;54(5):791-804. doi: 10.1016/j.molcel.2014.03.047.
Jun Yan 1,  Feng Yan 1,  Zhijun Li 1,  Becky Sinnott 2,  Kathryn M Cappell 2,  Yanbao Yu 3,  Jinyao Mo 4,  Joseph A Duncan 5,  Xian Chen 3,  Valerie Cormier-Daire 6,  Angelique W Whitehurst 2,  Yue Xiong 7
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
  • 2 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
  • 3 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
  • 4 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
  • 5 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.
  • 6 University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants-Malades, 75015 Paris, France.
  • 7 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: [email protected].
PMID: 24793695 DOI: 10.1016/j.molcel.2014.03.047
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.

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