Control of centrosome biogenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Centrosomes are minute multifunctional membrane-less organelles present in only two copies in a typical cycling animal cell. In the core of a centrosome is a nine-fold symmetrical cylindrical microtubule-based structure called a centriole. The centriole organizes the second major part of the centrosome, called pericentriolar material, which is a large and dynamic multiprotein complex and the site of most centrosomal functions. Centrosomes perform vital cellular functions such as microtubule nucleation, organization of the bipolar mitotic spindle pole during cell division, and cellular signaling, and they influence tissue architecture and cell motility. Centrioles also organize sensory and motile cilia, which are critically important for development and tissue homeostasis. Supernumerary and/or structurally aberrant centrioles and centrosomes can initiate tumorigenesis, promote tumor invasiveness, and are present in almost all types of tumors. Centriolar or ciliary defects are, in addition, an underlying cause of genetic disorders known as ciliopathies. Our current research focuses on understanding the molecular mechanisms that regulate centriole and centrosome numbers in healthy and pathological conditions and on deciphering their architecture at high resolution. Recently, we focused on elucidating the dynamics of a centrosomal protein CPAP (also known as CENPJ). We have characterized centriolar defects that occur under suboptimal levels of CPAP protein, which include the lack of complete centriole walls, structural instability, and 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. In another line of investigation, we dissected centrosomal localization of centrosome-forming kinase Plk4 at nano-scale resolution. We build a precise distribution map of Plk4 and its receptor Cep152 and Cep44, Cep192, and Cep152-anchoring factors Cep57 and Cep63. Centriole duplication is a highly regulated process driven by Polo-like kinase 4 (Plk4) and a few conserved initiators. Dissecting how Plk4 and its receptors organize within centrosomes is critical to understand centriole biogenesis. We have also explored how various cell cycle kinases (Plk1, Cdk2, Plk4), which are frequently upregulated in cancer, regulate centriole and centrosome number, ensure centriole and centrosome homeostasis, and how their dysregulation leads to their aberrant amplification and reduplication. Finally, we studied the basic principles of centriole elongation in human cells. Proper centriole structuring is a prerequisite for proper centrosome and cilia functioning. However, strikingly little is still known about the mechanisms that regulate centriole assembly. Specifically, we are exploring how individual cell cycle regulators affect centriole elongation during specific parts of the cell cycle. The final goal of this study is to understand how healthy cells maintain relatively uniform centriole and centrosome size and to identify how structurally defective centrioles and centrosomes occur in tumors. Manuscripts describing our recent findings are being published or are in preparation for publication.