Control of centrosome biogenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Centrosomes are small, multifunctional, membrane-less organelles present in only two copies in a typical cycling animal cell. A centrosome's structural core is a nine-fold symmetrical cylindrical microtubule-based structure called a centriole. The centriole organizes the second major part of the centrosome, known as pericentriolar material, which is a large and dynamic multiprotein complex responsible for most centrosome's functions. Centrosomes perform vital cellular roles, including microtubule nucleation and organization, organization of the apparatus for cell division (the mitotic spindle), cellular signaling, organization of tissue architecture, and cell motility. Centrioles also organize sensory and motile cilia, which are critically important for development and tissue homeostasis. Supernumerary and structurally aberrant centrioles and centrosomes can initiate tumorigenesis and promote tumor invasiveness. Notably, almost all investigated types of tumors harbor aberrant centrosomes. Centriolar or ciliary defects are also an underlying cause of genetic disorders known as ciliopathies. Our research program focuses on understanding the molecular mechanisms that regulate centriole and centrosome numbers in both healthy and pathological conditions. We also apply state-of-the-art microscopy methods (electron and super-resolution microscopy, live cell imaging, expansion microscopy) to dissect the molecular organization of the centrosomes. Our recent (published) studies resulted in a detailed molecular mapping of the centriole's distal appendages (assemblies critical for cilia formation and signaling). Further, the centriole duplication cycle is a highly regulated process in which cells ensure that the proper number of centrosomes is formed and maintained throughout cell generations. This process is driven by Polo-like kinase 4 (Plk4) and a few conserved initiators. We generated a nano-scale map of Plk4, its receptor Cep152, and Cep152-anchoring factors Cep57 and Cep63. Dissecting how Plk4 and its receptors organize within centrosomes is critical to understanding centriole biogenesis. We elucidated the dynamics of a centrosomal protein CPAP (also known as CENPJ) and characterized centriolar defects that occur under suboptimal levels of CPAP protein (which include the lack of complete centriole walls, structural instability, and centriole breakage). We have also demonstrated that CPAP is highly dynamic within the centriole but may not directly participate in the formation of mitotic spindles and cell division, as previously suggested. Our ongoing efforts are focused on understanding how cell cycle kinases (such as Plk1, Cdk2, and Cdk1) control the centriole and centrosome number. These kinases are frequently upregulated in cancers in association with centrosome aberrant phenotypes. Parts of this work are in preparation for publication. Another current focus is to understand the basic principles of centriole elongation in human cells. Proper centriole assembly is a prerequisite for the normal functioning of the centrosome and cilia. However, a significant gap remains in understanding how centrioles form. The far-reaching goal of this study is to understand how healthy cells maintain relatively uniform centriole and centrosome sizes and to identify the mechanisms by which structurally defective centrioles and centrosomes occur in tumors and centrosome-associated diseases. We have dissected the dynamics of centriole assembly during unperturbed cell cycles in high resolution and shown how individual cell cycle regulators influence centriole elongation. The manuscript is in preparation, describing these findings.