Co-workers:

We are studying the molecular mechanisms that ensure the accurate segregation of chromosomes during cell division. 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 of chromosome segregation we employ the distantly related budding and fission yeasts as model systems.

The partitioning of the genetic material into daughter cells begins with the duplication of the chromosomes. Coupled to the synthesis of an exact copy of the DNA is the assembly of protein complexes that are important for chromosome structure and organization. One such protein complex is the cohesin complex that holds the two newly duplicated chromosomes together. For accurate chromosome segregation during mitosis, the sister chromatids must capture microtubules from opposite poles. The kinetochore assembles on the centromere of each chromosome to connect them to microtubules. Cohesin resists the pulling forces of microtubules to allow all the chromosomes to make proper bipolar attachments. Once this has occurred, cohesin is abruptly lost, triggering the movement of identical sister chromatids to opposite poles. Cohesin is present along the chromosomes but is most highly enriched in a large domain surrounding the centromere, known as the pericentromere.

Our overall goal is to understand the composition and function of the pericentromere. Work currently underway in the lab focuses on three overlapping questions.

1. How is cohesin established in the pericentromere?

We identified a subcomplex in the budding yeast kinetochore that is important for cohesin enrichment in the pericentromere. We are currently investigating the mechanism by which cohesin is recruited and maintained at the pericentromere both in budding and fission yeast.

2. How does the pericentromere regulate the onset of anaphase?

A pericentromeric protein, Shugoshin, functions in a surveillance mechanism that prevents anaphase onset until all sister chromatids have made proper bipolar attachments. We aim to understand the role of Shugoshin in sensing the lack of tension associated with incorrect attachments and in signalling these errors to the cell cycle machinery.

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, the configuration of the chromosomes must change compared to mitosis because it is the maternal and paternal chromosomes that are segregated, rather than the sister chromatids. Our goal is to identify these changes through proteomic and genomic screens.

Selected publications:

Bizzari, F. and Marston, A.L. (2011) Cdc55 coordinates spindle assembly and chromosome disjunction during meiosis. J Cell Biol. 193, (7)1213-28 .

Fernius, J. and Marston, A.L. (2009) Establishment of cohesion at the pericentromere by the Ctf19 kinetochore subcomplex and the replication fork-associated factor, Csm3. PLoS Genet. e1000629.

Clift, D., Bizzari, F. and Marston, A.L. (2009) Shugoshin prevents cohesin cleavage by PP2ACdc55-dependent inhibition of separase. Genes Dev 23, 766-80.