Chromatin Remodeling Proteins Interact with Pericentrin to Regulate Centrosome Integrity □ D □ V

Program in Molecular Medicine, University of Massachusetts, Worcester, MA 01605, USA.
Molecular Biology of the Cell (Impact Factor: 4.47). 10/2007; 18(9):3667-80. DOI: 10.1091/mbc.E06-07-0604
Source: PubMed


Pericentrin is an integral centrosomal component that anchors regulatory and structural molecules to centrosomes. In a yeast two-hybrid screen with pericentrin we identified chromodomain helicase DNA-binding protein 4 (CHD4/Mi2beta). CHD4 is part of the multiprotein nucleosome remodeling deacetylase (NuRD) complex. We show that many NuRD components interacted with pericentrin by coimmunoprecipitation and that they localized to centrosomes and midbodies. Overexpression of the pericentrin-binding domain of CHD4 or another family member (CHD3) dissociated pericentrin from centrosomes. Depletion of CHD3, but not CHD4, by RNA interference dissociated pericentrin and gamma-tubulin from centrosomes. Microtubule nucleation/organization, cell morphology, and nuclear centration were disrupted in CHD3-depleted cells. Spindles were disorganized, the majority showing a prometaphase-like configuration. Time-lapse imaging revealed mitotic failure before chromosome segregation and cytokinesis failure. We conclude that pericentrin forms complexes with CHD3 and CHD4, but a distinct CHD3-pericentrin complex is required for centrosomal anchoring of pericentrin/gamma-tubulin and for centrosome integrity.

Download full-text


Available from: Sambra Redick, Dec 26, 2014
15 Reads
  • Source
    • "Other examples of functional links between the centrosome and the nucleus are already present in literature. CHD3 and CHD4, which belong to the nucleosome remodeling deacetylase (NuRD) complex, interact with pericentrin to regulate centrosome integrity [47]. These results, if functionally validated, may reveal new roles for ciliary-associated transcripts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Cilia are microtubule-based organelles protruding from almost all mammalian cells which, when dysfunctional, result in genetic disorders called “ciliopathies”. High-throughput studies have revealed that cilia are composed of thousands of proteins. However, despite many efforts, much remains to be determined regarding the biological functions of this increasingly important complex organelle. Results We have derived an online tool, from a systematic network-based approach to dissect the cilia/centrosome complex interactome (CCCI). The tool integrates all current available data into a model which provides an “interaction” perspective on ciliary function. We generated a network of interactions between human proteins organized into functionally relevant “communities”, which can be defined as groups of genes that are both highly inter-connected and strongly co-expressed. We then combined sequence and co-expression data in order to identify the transcription factors responsible for regulating genes within their respective communities. Our analyses have discovered communities significantly specialized for delegating specific biological functions such as mRNA processing, protein translation, folding and degradation processes that had never been associated with ciliary proteins until now. Conclusions CCCI will allow us to clarify the roles of previously unknown ciliary functions, elucidate the molecular mechanisms underlying ciliary-associated phenotypes, and apply our knowledge of the functional roles of relatively uncharacterized molecular entities to disease phenotypes and new clinical applications. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-658) contains supplementary material, which is available to authorized users.
    BMC Genomics 08/2014; 15(1):658. DOI:10.1186/1471-2164-15-658 · 3.99 Impact Factor
  • Source
    • "Maintenance of genome integrity is an essential process facilitated in eukarya by the nucleoprotein structures of chromatin. Multiple disease states result from mutation or aberrant function of enzymes dedicated to formation and/or maintenance of normal chromatin architecture, including the Mi-2/NuRD complex (Chou et al.; Cohet et al.; Larsen et al.; Misteli; Polo et al.; Smeenk et al.; Sillibourne et al., 2007; Pegoraro et al., 2009). Our results highlight the quality control processes engaged to monitor appropriate chromatin assembly ensuring that cells stably maintain their genomes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During chromosome duplication, it is essential to replicate not only the DNA sequence, but also the complex nucleoprotein structures of chromatin. Pericentric heterochromatin is critical for silencing repetitive elements and plays an essential structural role during mitosis. However, relatively little is understood about its assembly and maintenance during replication. The Mi2/NuRD chromatin remodeling complex tightly associates with actively replicating pericentric heterochromatin, suggesting a role in its assembly. Here we demonstrate that depletion of the catalytic ATPase subunit CHD4/Mi-2β in cells with a dampened DNA damage response results in a slow-growth phenotype characterized by delayed progression through S phase. Furthermore, we observe defects in pericentric heterochromatin maintenance and assembly. Our data suggest that chromatin assembly defects are sensed by an ATM-dependent intra-S phase chromatin quality checkpoint, resulting in a temporal block to the transition from early to late S phase. These findings implicate Mi-2β in the maintenance of chromatin structure and proper cell cycle progression.
    Molecular biology of the cell 07/2011; 22(17):3094-102. DOI:10.1091/mbc.E11-03-0258 · 4.47 Impact Factor
  • Source
    • "Other chromatin regulators have been involved in cell cycle processes unrelated to their transcriptional function. For example, chromatin-remodeling proteins were also found at human centrosomes, where they regulate the recruitment of centrosomal proteins, microtubule organization, and cytokinesis (Sillibourne et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Upon prolonged activation of the spindle assembly checkpoint, cells escape from mitosis through a mechanism called adaptation or mitotic slippage, which is thought to underlie the resistance of cancer cells to antimitotic drugs. We show that, in budding yeast, this mechanism depends on known essential and nonessential regulators of mitotic exit, such as the Cdc14 early anaphase release (FEAR) pathway for the release of the Cdc14 phosphatase from the nucleolus in early anaphase. Moreover, the RSC (remodel the structure of chromatin) chromatin-remodeling complex bound to its accessory subunit Rsc2 is involved in this process as a novel component of the FEAR pathway. We show that Rsc2 interacts physically with the polo kinase Cdc5 and is required for timely phosphorylation of the Cdc14 inhibitor Net1, which is important to free Cdc14 in the active form. Our data suggest that fine-tuning regulators of mitotic exit have important functions during mitotic progression in cells treated with microtubule poisons and might be promising targets for cancer treatment.
    The Journal of Cell Biology 11/2010; 191(5):981-97. DOI:10.1083/jcb.201007025 · 9.83 Impact Factor
Show more