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Adele Marston

Co-workers:

Bonnie Alver, Rachael Barton, Julie Blyth, Weronika Borek, Colette Connor, Eris Duro, Stefan Galander, Bethany Harker, Katarina Jönsson, Vasso Makrantoni, Rebecca Plowman, Xue (Bessie)Su, Nadine Vincenten
Marston Lab

Orienting Chromosomes during Mitosis and Meiosis

Adele gives a brief overview of her research.

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 yeastcells 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 s 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 understand how inner kinetochore proteins and chromatin domains establish the cohesin-rich pericentromere.

2. How does the pericentromere regulate chromosome segregation?
Many of the regulatory functions of the pericentromere are conferred by the pericentromeric adaptor protein, shugoshin. We found that shugoshin recruits the chromosome-organising complex, condensin, to the pericentromere, suggesting that it may play an important role in directing the organisation of the pericentromere. We are testing this hypothesis and investigating mechanisms of shugoshin regulation in mitosis and meiosis.

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. Meiotic recombination generates linkages between the homologs, required for their accurate segregation. However, recombination within the pericentromere is a risk factor for aneuploidy and is suppressed in a wide range of species. We demonstrated that the inner kinetochore prevents crossover recombination within the pericentromere through at least two separate mechanisms. This work has paved the way for understanding how crossover recombination within the pericentromere leads to the formation of aneuploid gametes.

Selected publications:

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.
Sarangapani K, Duro E, Deng Y, de Lima Alves F, Ye Q, Opoku KN, Ceto S, Rappsilber J, Corbett KD, Biggins S, Marston AL and Asbury C (2014) Sister
kinetochores are mechanically fused during meiosis I in yeast. Science 346, 248-251.
Vincenten N, Kuhl, L-M, Lam I, Oke A, Kerr A, Hochwagen A, Fung J, Keeney S, Vader G and Marston AL (2016) The kinetochore controls crossover
recombination during meiosis. eLife doi: 10.7554 [Epub ahead of print].


 

1. The pericentromere is enriched in the chromosome-organising complexes, cohesin, condensin and the adaptorprotein, shugoshin.
2. Live cell assay to measure recombination in the pericentromere and chromosome arm.
3. Sister kinetochore fusion underlies monoorientation during meiosis I.