Eukaryotic genomes are packaged in chromosomes. Accurate chromosome replication is critical for genome stability, controlled cell proliferation and healthy ageing. In fact, genome instability is a hallmark of several inherited human disorders and age-related diseases ranging from primordial dwarfism disorders to neurodegeneration and cancer.

Central to the process of genome replication are molecular machines called replisomes, which couple DNA unwinding to DNA synthesis. In every cell cycle, replisomes encounter naturally occurring ‘obstacles’ that can block replication and have the potential to induce genome instability. Fortunately, eukaryotes have evolved many mechanisms to ensure that their genomes are faithfully duplicated. These mechanisms include precise control of the assembly of replisomes and replication-associated stabilisation/repair processes that allow obstacles to be safely overcome. Whilst many factors involved in replisome assembly and obstacle bypass are known, their mechanisms of action remain obscure.

To understand how genome stability is maintained during DNA replication, the Miller group aim to determine the molecular mechanisms of replisome assembly and faithful chromosome replication. To do this, we apply a combination of biochemical, biophysical and structural techniques, including in vitro reconstitution of DNA replication and a novel, time-resolved, electron microscopy-based ‘visual biochemistry’ approach.

We are now looking for highly motivated BSc, MSc or Erasmus project students to join our team in investigating the mechanisms of faithful genome replication. In our group, you will have the opportunity to develop skills in molecular biology, the purification and biophysical characterisation of macromolecular machines, and cryo-EM. You will participate in the design, execution and interpretation of experiments, with training and support from an experienced postdoc mentor. The research projects will be overseen by Assoc. Prof. Thomas Miller, building on the experimental strategies developed in his recent study of replicative MCM helicase loading (Miller et al, Nature, 2019; further references can also be found on the group’s website: https://icmm.ku.dk/english/research-groups/miller-group/).

The research environment

The CCS is a Center of Excellence funded by the Danish National Research Foundation (DNRF) and its mission is to advance our understanding of how chromosomal instability causes human disease. The CCS is embedded at the Department of Cellular and Molecular Medicine (www.icmm.ku.dk) and offers a creative and stimulating working environment with a dynamic, collaborative and international atmosphere. Our research facilities include modern laboratories and access to state-of-the-art equipment including Titan Krios and Glacios electron microscopes for single particle EM, and C-trap optical tweezers for single-molecule biochemical and biophysical studies.

For more information about the project, please contact Tom Miller (tmiller@sund.ku.dk).