Cdc48/VCP Promotes Chromosome Morphogenesis by Releasing Condensin from Self-Entrapment in Chromatin

• Published in: Molecular cell 2018-02, Vol.69 (4), p.664-676.e5
• Main Authors: Thattikota, Yogitha, Tollis, Sylvain, Palou, Roger, Vinet, Justine, Tyers, Mike, D’Amours, Damien
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Cdc48; chromatin; Chromatin Assembly and Disassembly; chromosome condensation; Chromosomes, Fungal - genetics; Chromosomes, Fungal - metabolism; condensin; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; genome stability; Mitosis; Morphogenesis; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; SMC; Ufd1-Npl4; Valosin Containing Protein - genetics; Valosin Containing Protein - metabolism; VCP
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.01.030

The morphological transformation of amorphous chromatin into distinct chromosomes is a hallmark of mitosis. To achieve this, chromatin must be compacted and remodeled by a ring-shaped enzyme complex known as condensin. However, the mechanistic basis underpinning condensin’s role in chromosome remodeling has remained elusive. Here we show that condensin has a strong tendency to trap itself in its own reaction product during chromatin compaction and yet is capable of interacting with chromatin in a highly dynamic manner in vivo. To resolve this apparent paradox, we identified specific chromatin remodelers and AAA-class ATPases that act in a coordinated manner to release condensin from chromatin entrapment. The Cdc48 segregase is the central linchpin of this regulatory mechanism and promotes ubiquitin-dependent cycling of condensin on mitotic chromatin as well as effective chromosome condensation. Collectively, our results show that condensin inhibition by its own reaction product is relieved by forceful enzyme extraction from chromatin. [Display omitted] •The condensin complex is the main effector of chromosome condensation in mitosis•Chromatin accessibility is reduced when chromosomes are compacted by condensin•The Cdc48/VCP segregase stimulates condensin release from compacted chromatin•Condensin must maintain high mobility on mitotic chromatin to promote condensation During mitosis, chromatin is reorganized into a more compact, less accessible configuration. The authors found that the main effector of the compaction process—condensin—requires a special “segregase activity” to transit effectively through mitotic chromatin. CDC48/VCP encodes the essential segregase that enhances condensin mobility and compaction activity on mitotic chromosomes.