M.S. Moscow State University
Ph.D. Moscow State University
We are interested in the mechanics of cell division (mitosis). The goal of mitosis is to equally segregate genetic material between the two daughter cells. To achieve this goal cells rely on a self-assembling molecular machine known as the mitotic spindle. The spindle contains three principal elements: centrosomes, chromosomes, and microtubules. Our research is aimed at determining the rules and mechanisms of interactions between these principle components. We use sophisticated imaging techniques to follow movements of chromosomes and centrosomes and to reveal their fine structural organization. We also make an extensive use of a special approach, laser microsurgery, that allows us to instantly and specifically ablate intracellular components inside a live cell. Laser microsurgery has revealed several surprises in the mechanisms of mitotic spindle formation. For example, although centrosomes are traditionally viewed as the principal microtubule-organizing centers of the cell, mitotic spindle can assemble even when both centrosomes are completely ablated by the laser. Laser microsurgery also allowed us to describe an intriguing new mechanism of centriole assembly. Centrioles are structural organizers of the centrosome and their number determines of number of centrosomes present in the cell. For a very long time it was believed that centrioles in animal somatic cells can propagate only via templated duplication. In this mechanism a new ‘daughter’ centriole forms in association with the mature ‘mother’ centriole. The significance of this mechanism that resembled DNA replication was not understood. Our laser microsurgery experiments demonstrated that complete ablation of mother centrioles does not prevent formation of daughter centrioles from scratches (i.e., de novo). In fact, the de novo pathway results in simultaneous formation of numerous (up to 14) centrioles. Thus, it appears that the role of mother centrioles during centriole duplication is to restrict the number of daughters that form in a single cell cycle. This mechanism has important biomedical ramifications because supernumerary centrioles are often observed in cancers, although their origin in cancerous cells remains elusive.
The role of centrosomes in mitotic spindle formation and the mechanism of centriole de novo assembly remain in the focus of our current research projects.
C. O’Connell, J. Loncarek, P. Hergert, A. Kourtidis, D.S. Conklin, and A. Khodjakov. 2008. The spindle assembly checkpoint is satisfied in the absence of interkinetochore tension during mitosis with unreplicated genomes. J. Cell. Biol., 183:29-36 (Featured in JCB; Faculty of 1000 rating “Must read”)
J. Lončarek, P. Hergert, V. Magidson, and A. Khodjakov. 2008. Control of daughter centriole formation by the pericentriolar material. Nat. Cell Biol., 10:322-328 (with journal cover. Featured in NCB “News & Views; “Faculty of 1000” rating “Must read”)
J. Lončarek, O. Kisurina-Evgenieva, T. Vinogradova, P. Hergert, S. La Terra, T.M. Kapoor, and A. Khodjakov. 2007. The centromere geometry essential for keeping mitosis error free is controlled by spindle forces. Nature, 450:745-749 (with journal cover. Featured in Curr. Biol.; “Faculty of 1000” rating “Exceptional”).
Y. Dong, K.J. VandenBeldt, X. Meng, A. Khodjakov, and B.F. McEwen. 2007. The outer plate in vertebrate kinetochores is a flexible network with multiple microtubule interactions. Nat. Cell Biol., 9:516-522 (with journal cover. “Faculty of 1000”rating “Must Read”).
Magidson, V., F. Chang, and A. Khodjakov. 2006. Regulation of cytokinesis by spindle pole bodies. Nat. Cell Biol., 8:891-893.
Kapoor, T.M., M. Lampson, P. Hergert, L. Cameron, D. Cimini, E.D. Salmon, B.F. McEwen, and A. Khodjakov. 2006. Chromosomes can congress to the metaphase plate prior to bi-orientation. Science, 311:388-391. (with journal cover. Featured in Science, Nature, Nature Reviews, JCB, J. Chem. Biol. “Faculty of 1000”rating “Exceptional”)