Orienting chromosomes during mitosis and meiosis
Our goal is to understand the molecular mechanisms that ensure the accurate transmission of chromosomes to daughter cells during cell division. Errors in chromosome segregation generate cells with the wrong number of chromosomes, known as aneuploidy. Aneuploid somatic cells, arising as a result of errors in mitosis, are associated with cancer. Aneuploid gametes are generated from erroneous meiosis and are causative for miscarriages, infertility and birth defects. We aim to uncover conserved and fundamental mechanisms in both mitosis and meiosis by employing yeast cells and frog oocytes as models, together with a wide range of cell biological and biochemical methodologies.
A central theme of current work in our laboratory is non-canonical roles of the kinetochore. The kinetochore is a complex molecular machine that assembles on the centromere and is best known for its role in coupling chromosomes to microtubules, thereby mediating the movement of chromosomes. Our work has uncovered key regulatory and structural functions of the kinetochore that impinge on various aspects of chromosome segregation:
1. Chromosome organisation We showed that the kinetochore targets cohesin loading to the centromere through a dedicated pathway that enriches cohesin throughout the surrounding chromosomal region (the pericentromere). We uncovered the mechanism of this targeted cohesin loading (Figure 1) and demonstrated its importance for chromosomal organisation in this region (Figure 2).
2. Cell cycle regulation Shugoshin is a pericentromeric adaptor protein that performs multiple distinct functions in chromosome segregation during mitosis and meiosis. We showed that shugoshin delocalizes from the pericentromere to indicate that chromosomes are properly attached to microtubules, called biorientation. Our recent work has uncovered a regulatory pathway that inactivates shugoshin, to allow cell cycle progression once biorientation has been achieved.
3. Adaptations for meiosis Meiosis is a modified cell division that produces gametes through two consecutive rounds of chromosome segregation. During the first meiotic division, uniquely, the maternal and paternal chromosomes or homologs are segregated. This requires several adaptations to the way in which chromosomes are segregating including the way in which chromosomes attach to the microtubules that will pull them apart, and the way in which linkages between them are lost. Our recent work has revealed how a master meiosisI-specific regulator establishes these modifications, essentially converting mitosis into meiosis. In addition, we have uncovered aspects of kinetochore assembly and function that are critical for meiosis, but not mitosis. Our future focus is to gain a thorough understanding of how kinetochores are adapted for meiosis both in yeast and vertebrates.
Blyth J, Makrantoni V, Barton RE, Spanos C, Rappsilber J and Marston AL. (2018) Genes Important for Schizosaccharomyces pombe Meiosis Identified Through a Functional Genomics Screen. Genetics. 208, 589-603.
Hinshaw SM, Makrantoni V, Harrison SC and Marston AL (2017) The Kinetochore Receptor for the Cohesin Loading Complex. Cell 171, 72-84
Fox C, Zou J, Rappsilber J and Marston AL. (2017) Cdc14 phosphatase directs centrosome re-duplication at the meiosis I to meiosis II transition in budding yeast. Wellcome Open Res. doi: 10.12688/wellcomeopenres.10507.1.