The Molecular Basis of Sister Chromatid Cohesion

Cohesion between sister chromatids, mediated by the chromosomal cohesin complex, is a prerequisite for faithful chromosome segregation during cell division.

The ring-shaped cohesin complex is a multisubunit ATPase that topologically loads onto DNA in the G1 phase of the cell cycle. The first part of the proposal will elucidate the molecular mechanism of cohesin function.

We will employ and develop biophysical, structural and DNA-protein crosslink mass spectrometry tools to map the trajectory by which DNA enters the cohesin ring, fuelled by ATP-dependent conformational changes. The second part of the proposal examines the establishment of sister chromatid cohesion during S phase.

We will investigate how, as the replication fork moves along DNA, cohesin transitions from containing one DNA to embracing two newly replicated DNAs.

This includes the functional characterisation of replisome components with roles in sister chromatid cohesion, known as ‘cohesion establishment factors’.

Furthermore, we will take advantage of recent success with the biochemical reconstitution of complete DNA replication and work towards recapitulating sister chromatid cohesion establishment in vitro. This will open unique experimental opportunities to understand the process.

Together, this programme will provide insight into the molecular mechanism of how cohesin safeguards faithful chromosome segregation.