Nikola Dzhindzhev

Centrosomes are cellular organelles whose primary function is to nucleate and organise the microtubule (MT) cytoskeleton in cells. They are especially important during cell division for assembly and orientation of the mitotic spindle - the machine that ensures proper segregation of chromosomes to the two daughter cells. The significance of centrosomes for correct cell division has recently been highlighted by publications showing that centrosome deregulation can lead to tumorigenesis. A centrosome consists of a pair of orthogonally oriented cylindrical structures called centrioles and a surrounding cloud of pericentriolar material (PCM), which is believed to consist mainly of MT-associated proteins and gamma-tubulin complexes - the main MT nucleation factors in cells. I use Drosophila as a model system to study two key centrosome processes and their regulation: Centrosome maturation and centrosome duplication. Centrosome maturation is the process of recruitment and accumulation of PCM around centrioles at the beginning of mitosis. As a consequence of this centrosomes become much more potent MT nucleating and organising centres, which is required for them to be able to assemble the mitotic spindle. I concentrate on two molecules that have been shown to be essential for this process both in Drosophila and in mammalian systems, Centrosomin (Cnn) and Polo kinase. The question that I try to answer is: How these two factors regulate centrosome maturation and what is the nature of their relationship? My approach is to first identify centrosomal partners of Cnn and Polo and potential Polo substrates and then to test whether they are also required for centrosome maturation and how. I have so far identified several conserved centrosomal proteins, which interact in vivo and in vitro with Cnn. I am currently performing functional analysis (both genetic and biochemical) of these interactors in collaboration with Dr Eva Wegel and Dr Guojie Mao from our group. The centrosome duplication cycle is a heavily regulated process. It is tightly coupled to the cell division cycle to ensure that centrosomes duplicate only once per cell cycle and that only one daughter centriole emerges next to each mother centriole. Work from both our group and from other laboratories has shown that one of the key master regulators of centrosome duplication is the Polo-like kinase 4 (Plk4). In order to study how Plk4 controls this process we have identified biochemical interactors and putative substrates of this kinase. My current work together with graduate student Dawn Yu on these interactors is yielding interesting results and promises to shed more light on the molecular mechanisms that govern centrosome duplication.

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