Orienting chromosomes during mitosis and meiosis
The overall goal of work in our lab is to understand how chromosomes are accurately segregated during cell division. What are the mechanisms that ensure daughter cells receive an identical set of chromosomes to the parental cell during mitosis? How are these controls adapted to halve the number of chromosomes and generate gametes through meiosis? Errors in chromosome segregation generate daughter cells with the wrong number of chromosomes, known as aneuploidy, and this is associated with cancer, birth defects and infertility. To uncover conserved and fundamental mechanisms we employ yeast cells and frog oocytes as model systems together with a wide range of cell biological and biochemical methodologies.
We are focused on the regulatory role of the pericentromere and adaptations to the kinetochore during meiosis. The kinetochore is a complex molecular machine that assembles on the centromere and couples chromosomes to microtubules. The pericentromere is a specialized chromosomal domain that surrounds the centromere, is highly enriched in the chromosome-linking cohesin complex and plays multiple critical roles in ensuring the accuracy of chromosome segregation. The pericentromeric adaptor protein, shugoshin, builds a regulatory platform that monitors segregation.
We aim to address three broad questions:
1. How is cohesin established in the pericentromere?
We demonstrated that a dedicated cohesin loading pathway operates at the centromere to enrich cohesin throughout the pericentromere. Our current focus is to determine how cohesin shapes the pericentromere and understand the importance of pericentromere structure in chromosome segregation.
2. How does the pericentromere regulate chromosome segregation?
Shugoshin is a pericentromeric adaptor protein that performs multiple distinct functions in chromosome segregation during mitosis and meiosis. We aim to understand the regulatory pathways that underlie these functions.
3. How is the pericentromere modified 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 chromosomes including the manner of attachment to the microtubules that will pull them apart and the timing with which the linkages between them are lost. Using yeast cells and frog oocytes we are elucidating the molecular modifications to the chromosome segregation machinery that are required to sort chromosomes accurately into gametes.
Fox C, Zou J, Rappsilber J, 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.
Hinshaw SM, Makrantoni V, Kerr A, Marston AL and Harrison SC (2015) Structural evidence for Scc4-dependent localization of cohesin loading. eLife doi: 10.7554/eLife.06057.
Vincenten N, Kuhl, L-M, Lam I, Oke A, Kerr A, Hochwagen A, Fung J, Keeney S, Vader G and Marston AL (2015) The kinetochore controls crossover recombination during meiosis. eLife doi: 10.7554