Professor Tomo Tanaka FRSE
To maintain genetic integrity, eukaryotic cells must segregate their duplicated chromosomes to their daughter cells with high fidelity during mitosis. The unravelling of the mechanisms ensuring proper chromosome segregation should improve our understanding of various human diseases such as cancers and congenital disorders, which are characterized by chromosome instability and aneuploidy.
We study both budding yeast and human cells, taking advantages of both systems. Basic mechanisms of chromosome regulation are well conserved from yeast to humans. With yeast cells, we can set up experiments and get results quickly, whereas with human cells, we can obtain information more directly relevant to human health and disease. We are currently focusing on the following research topics:
1) Kinetochore-microtubule interaction in mitosis
Kinetochores are large protein complexes formed at the centromere regions of chromosomes. For high-fidelity chromosome segregation, kinetochores must be properly caught on the mitotic spindle (reviewed in Tanaka TU 2010). We have found that kinetochores initially interact with the lateral surface of a single microtubule extending from a spindle pole (Figure 1, step 2; Tanaka K et al, 2005, Kitamura et al, 2007); this process is often facilitated by microtubules generated at kinetochores (Figure 2, step 1; Kitamura et al, 2010). Subsequently kinetochores are tethered at the microtubule plus ends (Figure 1, step 3; Figure 2; Tanaka K et al, 2007; Maure et al, 2011; Kalantzaki et al 2015). When this process fails, a failsafe mechanism prevents kinetochore detachment from a microtubule (Figure 2; Gandhi et al, 2011).
Following the initial interaction with microtubules, sister kinetochores must interact with microtubules extending from opposite spindle poles (sister kinetochore bi-orientation) before anaphase onset (Figure 1, step 6). If this interaction occurs with aberrant orientation (Figure 2, step 4), such errors must be corrected by turnover of the kinetochore–microtubule attachment (error correction; Figure 2, step 5). We have found that Aurora B/Ipl1 kinase and other factors have crucial roles in this process (Figure 3; Dewar et al, 2004; Maure et al, 2007; Keating et al, 2009; Kalantzaki et al 2015). We are investigating these mechanisms in more detail in vivo in yeast and also by reconstituting kinetochore–microtubule interaction in vitro, and by extending our study from yeast to human cells.
2) Sister chromatid cohesion and chromosome compaction
Duplicated chromosomes (sister chromatids) are held together by sister chromatid cohesion until chromosome segregation takes place in anaphase. Without this cohesion, there would be no way to mark a pair of sister chromatids destined for segregation. In particular, robust sister chromatid cohesion around kinetochores is crucial for this purpose. We recently found that this robust cohesion is facilitated by Dbf4-dependent kinase recruited to kinetochores (Figure 4; Natsume et al, 2013). We are currently studying this mechanism in more detail.
For chromosome segregation, sister chromatid cohesion must be removed. Our recent study has revealed how removal of cohesion is completed during early anaphase in yeast (Renshaw et al, 2010). This process is coupled with chromosome recoiling/compaction. We assume similar regulation is present during prophase in human cells and are current testing this possibility.
Figure 1. The figure illustrates step-wise development of kinetochore–microtubule interactions in mitosis (prometaphase [steps 1-5] and metaphase [step 6]) (reviewed in Tanaka TU 2010).
Figure 2. Molecular mechanisms involved in kinetochore tethering at the microtubule end (Maure et al, 2011; Kalantzaki et al, 2015) and in the failsafe procedure preventing kinetochore detachment from a microtubule (Gandhi et al, 2011).
Figure 3. The aberrant kinetochore–microtubule attachment is removed by the action of Aurora B kinase. Aurora B differentially regulates lateral attachment and end-on attachment, which drives the error correction process (Kalantzaki et al, 2015).
Figure 4. Kinetochores not only promote microtubule attachment but also facilitate robust cohesion and advance replication timing of surrounding regions. Dbf4–Cdc7
A) Lectures and tutorials for undergraduate students about chromosome segregation in mitosis
Level 3 (BS31006 Gene Regulation and Expression)
Level 4 (BS42010 Advanced Gene Regulation and Expression)
B) Supervisor of Honours degree students
C) Supervisor of PhD students
D) Coordinator of PhD student induction program
Major publications from the group
Yue, Z., Komoto, S. Gierlinski, M., Pasquali, D., Kitamura, E and Tanaka, T.U. (2017) Mechanisms mitigating problems associated with multiple kinetochores on one microtubule in early mitosis. J. Cell. Sci. 130, 2266-2276. PMID:28546446; DOI 10.1242/jcs.203000. view paper
Vasileva, V., Gierlinkski, M., Yue, Z., O'Reilly, N., Kitamura, E. and Tanaka, T.U. (2017) Molecular mechanisms facilitating the initital kinetochore encounter with spindle microtubules. J. Cell Biol., 216, 1609-22. doi: 10.1083/jcb.201608122; PMID:28446512. view paper
Kalantzaki, M., Kitamura, E., Zhang, T., Mino, A., Novák, B. and Tanaka, T. U. (2015) Kinetochore-microtubule error correction is driven by differentially regulated interaction modes. Nature Cell Biology, 17, 421-433.
doi; 10.1038/ncb.3128.; PMID: 25751138 View Paper
Kobayashi, N., Suzuki, Y., Schoenfeld, L. W., Müller, C. A., Nieduszynski, C., Wolfe, K. H. and Tanaka, T. U. (2015) Discovery of an unconventional centromere in budding yeast redefines evolution of point centromeres. Curr Biol 25; 2026-33. doi; 10.1016/j.cub.2015.06.023; PMID: 26166782 View Paper
Tanaka, T.U., Clayton, L., Natsume, T. (2013) Three wise centromere functions: see no error, hear no break, speak no delay. EMBO Rep, 14, 1073-83. doi; 10.1038/embor.2013.181. PMID: 24232185 View Paper
Natsume, T., Müller, C. A., Katou, Y., Retkute, R., Gierlinski, M., Araki, H., Blow, J. J., Shirahige, K., Nieduszynski, C. A. and Tanaka, T. U. (2013) Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment. Mol Cell, 50, 661-74. (2013). doi; 10.1016/j.molcel.2013.05.011; PMID: 23746350 View Paper
Saner, N., Karschau, J., Natsume, T., Gierlinski, M., Retkute, R., Hawkins, M., Nieduszynski, C. A., Blow, J. J, de Moura, A. P. S. and Tanaka, T. U. (2013) Stochastic association of neighboring replicons creates replication factories in budding yeast. J Cell Biol, 202, 1001-12. doi; 10.1083/jcb.201306143; PMCID: PMC3787376 View Paper
Gandhi, S. R, Gierlinski, M., Mino, A., Tanaka, K., Kitamura, E., Clayton, L. and Tanaka, T. U. (2011) Kinetochore-dependent microtubule rescue ensures their efficient and sustained interactions in early mitosis. Dev Cell, 21, 920-33. doi; 10.1016/j.devcel.2011.09.006.; PMID: 22075150 View Paper
Maure, J-F.*, Komoto, S.*, Oku, Y., Mino, A., Pasqualato, S., Natsume, K., Clayton, L., Musacchio, A. and Tanaka, T. U. (2011) The Ndc80 loop region facilitates formation of kinetochore attachment to the dynamic microtubule plus end. Curr Biol, 21, 207-13. (* equal contribution) doi; 10.1016/j.cub.2010.12.050.; PMID: 21256019 View Paper
Kitamura, E.*, Tanaka, K.*, Komoto, S.*, Kitamura, Y., Antony, C. and Tanaka, T. U. (2010) Kinetochores generate microtubules with distal plus ends: their roles and limited lifetime in mitosis. Dev Cell, 18, 248-59. (* equal contribution) doi; 10.1016/j.devcel.2009.12.018.; PMID: 20159595 View Paper
Renshaw, M. J., Ward, J. J., Kanemaki, M., Natsume, K., Nedelec, F. J. and Tanaka, T. U. (2010) Condensins promote chromosome recoiling during early anaphase to complete sister chromatid separation. Dev Cell, 19, 232-44. doi; 10.1016/j.devcel.2010.07.013.; PMID: 20708586 View Paper
Tanaka, T. U. (2010) Kinetochore-microtubule interactions: steps towards bi-orientation. Embo J, 29, 4070-82. doi; 10.1038/emboj.2010.294; PMID: 21102558 View Paper
Kitamura, E., Tanaka, K., Kitamura, Y. and Tanaka, T. U. (2007) Kinetochore-microtubule interaction during S phase in Saccharomyces cerevisiae. Genes Dev, 21, 3319-30.
doi; 10.1101/gad.449407; PMID: 18079178 View Paper
Maure, J-F., Kitamura, E. and Tanaka, T. U. (2007) Mps1 kinase promotes sister kinetochore bi-orientation by a tension-dependent mechanism. Curr Biol, 17, 2175-82.
doi; 10.1016/j.cub.2007.11.032; PMID: 18060784; View Paper
Tanaka, K., Kitamura, E., Kitamura, Y. and Tanaka, T. U. (2007) Molecular mechanisms of microtubule-dependent kinetochore transport towards spindle poles. J Cell Biol, 178, 269-81.
doi; 10.1083/jcb.200702141; PMID: 17620411 View Paper
Kitamura, E., Blow J. J. and Tanaka, T. U. (2006) Live-cell imaging reveals replication of individual replicons in eukaryotic replication factories. Cell, 125, 1297-308.
doi; 10.1016/j.cell.2006.04.041; PMID: 16814716 View Paper
Tanaka, K., Mukae, N., Dewar, H., van Breugel, M., James, E. K., Prescott, A. R., Antony, C. and Tanaka T. U. (2005) Molecular mechanisms of kinetochore capture by spindle microtubules. Nature 434, 987-94.
doi; 10.1038/nature03483; PMID: 15846338 View Paper
Dewar, H., Tanaka, K., Nasmyth, K. and Tanaka, T. U. (2004) Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle. Nature 428, 93-97. PMID: 14961024 View Paper
Errors in chromosome duplication or segregation generate cells with missing or excessive chromosomes (aneuploidy). Aneuploidy could cause various human diseases such as cancers and congenital disorders. It is therefore crucial to understand the molecular mechanisms ensuring proper chromosome duplication and segregation.