Frank Uhlmann

 

The molecular mechanism of chromosome segregation

Sister chromatid cohesion is the basis for the recognition of chromosomal DNA replication products for their bipolar segregation in mitosis. Fundamental to sister chromatid cohesion is the ring-shaped cohesin complex, which is loaded onto chromosomes well before the initiation of DNA replication and is thought to hold replicated sister chromatids together by topological embrace. What happens to cohesin when the replication fork approaches, and how cohesin recognises newly synthesised sister chromatids, are poorly understood. The characterization of a number of 'cohesion establishment factors' has started to provide hints as to the reactions involved. Cohesin is a member of the evolutionarily conserved family of Smc subunit-based protein complexes that contribute to many aspects of chromosome biology by mediating long-range DNA interactions. The establishment of sister chromatid cohesion may entail selective stabilisation of those cohesin-mediated DNA interactions that link sister chromatids in the wake of replication forks. How these are singled out and how cohesion establishment factors help the cohesin complex to hold together two strands of DNA, will be investigated. We use a combination of biochemical and molecular genetic approaches to approach these questions.

1. Rolef Ben-Shahar, T., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M. and Uhlmann, F. (2008)
Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.
Science 321: 563-566. PubMed abstract

2. Borges, V., Smith, D. J., Whitehouse, I. and Uhlmann, F. (2013)
An Eco1-independent sister chromatid cohesion establishment pathway in S. cerevisiae.
Chromosoma  122: 121-134. PubMed abstract

3. Murayama, Y. and Uhlmann, F. (2015)
DNA entry into and exit out of the cohesin ring by an interlocking gate mechanism.
Cell 163: 1628-1640. PubMed abstract>

4. Uhlmann, F. (2016)
SMC complexes: from DNA to chromosomes.
Nature Reviews Molecular Cell Biology 17: 399-412. PubMed abstract