CUL9 Mediates the Functions of the 3M Complex and Ubiquitylates Survivin to Maintain Genome Integrity

• Published in: Molecular cell 2014-06, Vol.54 (5), p.805-819
• Main Authors: Li, Zhijun, Pei, Xin-Hai, Yan, Jun, Yan, Feng, Cappell, Kathryn M., Whitehurst, Angelique W., Xiong, Yue
• Format: Article
• Language: English
• Subjects: Aneuploidy; Animals; Cell Death; Cullin Proteins - genetics; Cullin Proteins - metabolism; Cullin Proteins - physiology; Gene Knockdown Techniques; Genes, Tumor Suppressor; Genomic Instability; HCT116 Cells; Humans; Inhibitor of Apoptosis Proteins - metabolism; Liver - pathology; Mice; Mice, Knockout; Multiprotein Complexes - physiology; Polyploidy; Protein Multimerization; Repressor Proteins - metabolism; Ubiquitination
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.03.046

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. [Display omitted] •CUL9 functions in maintaining genomic integrity•CUL9 is a downstream effector of the 3M complex•CUL9 is an E3 ubiquitin ligase for survivin•Evidence for a functional 3M-CUL9-survivin pathway 3M genes CUL7, OBSL1, and CCDC8 regulate microtubule dynamics and cell division. Li et al. show that CUL9 mediates the function of the 3M genes and is an E3 ubiquitin ligase for survivin. These studies elucidate a pathway, the 3M pathway, for the maintenance of the genome integrity.