Patrick Meraldi

Chromosome movement and kinetochores: the key to chromosome segregation

Cell division relies on the precise duplication of chromosomes during DNA replication and their faithful transmission into two daughter cells during mitosis. Chromosome segregation is controlled by the mitotic spindle, which attaches and exerts forces on the chromosomes through microtubules (Figure 1). During this process each chromosome has to be bound by microtubules emanating from opposite spindle poles and has to be aligned on a metaphase plate. Microtubules bind to chromosomes through kinetochores, multiprotein complexes that assemble on centromeric DNA¹. Kinetochores provide three key functions during chromosome segregation: (1) they bind to microtubules in a tight yet dynamic manner. (2) They regulate and power chromosome movements. (3) They delay anaphase onset by activating the spindle assembly checkpoint in the presence of incorrect microtubule attachments². Kinetochore deregulation disrupts chromosome segregation and leads to aneuploidy, a hallmark of 80% of solid tumors in humans, suggesting a fundamental link to cancer formation^{3, 4}.

Figure 1: schematic model for the cell cycle of chromosome segregation. Chromosomes are indicated in blue, centrosomes are in purple, microtubles are in green and the sister kinetochore pairs are in red. On the right are shown as examples two human mitotic cells in metaphase and anaphase stained with for kinetochores, microtubules and chromatin. Scale bar = 10 micrometer

The goal of our laboratory is to understand in human cells how kinetochores exert force and drive chromosome movement to guarantee a faithful chromosome segregation, to understand the forces which determine mitotic spindle formation, orientation and architecture, to dissect the surveillance mechanisms that monitor chromosome segregation and activate the spindle checkpoint in the presence of unaligned chromosomes, and to understand how a deregulation of these processes can lead to aneuploidy and tumor formation. For this purpose we use a combination of high-resolution live cell microscopy techniques, RNA interference, and cell biological and biochemical assays. Our current activities focus on four specific subjects:

 

- Characterization of the CENP-A^NAC/CAD kinetochore network as a key requlator of kinetochore microtubule dynamics

- Investigating the assembly, dynamics and orientation of the mitotic spindle

- Monitoring and dissecting chromosome alignment using high resolution imaging assays

- Studying the role of the Bub1 protein kinase in spindle checkpoint and chromosome-microtubule attachment

 

Moreover, we are also in very close scientific contacts to other "mitosis" laboratories in the institute, in particular the groups of Yves Barral, Daniel Gerlich, Ulrike Kutay and Matthias Peter.

 

1. Santaguida, S. & Musacchio, A. The life and miracles of kinetochores EMBO J., 28, 2511-31 (2009)
2. Musacchio, A. & Salmon, E.D. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8, 379-393 (2007).
3. Draviam, V.M., Xie, S. & Sorger, P.K. Chromosome segregation and genomic stability. Curr Opin Genet Dev 14, 120-125 (2004).
4. Yuen, K.W., Montpetit, B. & Hieter, P. The kinetochore and cancer: what's the connection? Curr Opin Cell Biol 17, 576-582 (2005).