How cells regulate chromosome segregation in mitosis and how this goes wrong in cancer

Human cells store their genetic information in 46 chromosomes. To maintain this vital genetic information, a complete set of chromosomes must be inherited precisely by each daughter cell after cell division. Errors in this process cause cell death and various human diseases, such as spontaneous miscarriage during pregnancy, genetic abnormalities and cancers. Our research goal is to understand the fundamental mechanisms that ensure accurate chromosome inheritance when cells divide. These mechanisms concern how chromosomes undergo structural changes involving sister chromatid resolution and compaction in early mitosis and how chromosomes efficiently and correctly interact with the mitotic spindle that subsequently moves chromosomes into the new daughter cells.  

Our group has been studying molecular mechanisms for these processes, using budding yeast and human cells. While budding yeast represents a simple model system to study evolutionarily conserved mechanisms, human cells provide information directly relevant to human diseases. Our group’s pioneering works in budding yeast revealed how chromosomes efficiently interact with the mitotic spindle and how errors in this process are subsequently corrected [1]. Moreover, in human cells, our group recently discovered a novel mechanism that defines chromosome positioning to facilitate interaction with the mitotic spindle [2]. We also developed a novel assay to analyse the structural changes of human chromosomes during early mitosis in live cells [3].  

A PhD student taking this project will study further details of these crucial mechanisms regulating chromosomes in mitosis, using advanced live-cell imaging, biochemical approaches and mathematical modelling. The aim of the project is not only to understand mechanisms in normal cells, but also to reveal how the mechanisms go wrong, leading to chromosome instability in cancer cells. Through this project, they will learn the latest methods in molecular cell biology such as CRISPR/Cas9 genome editing, siRNA and Live FISH as well as state-of-the-art microscopy including super resolution live-cell imaging and advanced AI-based image analyses. 

References 

[1]   [1] Doodhi H., Kasciukovic T., Clayton L. & Tanaka T.U. Aurora B switches relative strength of kinetochore–microtubule attachment modes for error correction. J. Cell Biol. 220, e202011117 (2021). 

[2] Booth AJR et al. Contractile actomyosin network on nuclear envelope remnants positions chromosomes for mitosis. eLife 8, e46902 (2019). 

[3]   [3] Eykelenboom, J.K., Gierlinski, M., Yue, Z., Hegarat, N., Pollard, H., Fukagawa, T., Hochegger, H., & Tanaka, T.U. Live imaging of marked chromosome regions reveals their dynamic resolution and compaction in mitosis. J. Cell Biol. 218, 1531-52 (2019).