3.5 year MRC PhD Programme: Understanding how DNA repair nucleases remove chromosome tangles to prevent chromosomal instability and disease

The DNA in our cells is highly reactive, and as a result chromosomal DNA is damaged at high frequency. Consequently cells have evolved sophisticated mechanisms to detect and repair DNA damage. Failure to repair DNA damage can lead to mutations, which in turn causes human diseases such as cancer – this is one of the reasons why understanding how cells signal and repair DNA damage is so important. Another reason is that some of the most commonly used anti-cancer chemotherapy drugs exert their anti-tumour effects by inducing DNA damage. This is because cancer cells are more sensitive to the killing effects of DNA damage than normal cells. Cells have important mode of DNA repair known as homologous recombination (HR), for repairing DNA double-strand breaks and broken replication forks.

During HR DNA becomes tangled and knotted, as a normal part of the repair process, giving rise to structures such as Holliday junctions and other branched DNA structures. These chromosomal tangles must be removed prior to mitosis in order to permit chromosomes to segregate during cell division. A few years back we discovered a “molecular toolkit” – the SLX4 complex – that can remove Holliday junctions and other dangerous DNA structures from chromosomal DNA. The SLX4 complex comprises a scaffold protein (SLX4) and three different nucleases, enzymes that cleave DNA in a programmed way. Mutations in SLX4 cause the chromosomal instability syndrome Fanconi anemia, accompanied by developmental abnormalities, bone marrow failure and cancers. Therefore the ability of this complex to clear dangerous DNA repair intermediates from the genome is vital for health.

The project on offer involves studying how the activity of the SLX4 complex is kept in check in cells. It is important that DNA cleavage is restricted to the right place and time in the cell, to avoid inappropriate genome cleavage. The project will involve training in a wide range of cell and molecular biological techniques relevant to DNA damage signalling and repair including CRISPR-mediated genome editing, high-resolution confocal microscopy, as well as the analysis of protein phosphorylation and ubiquitylation.

The University of Dundee is delighted to be recruiting for five PhD studentships, funded for 3.5 years, to start in September 2017. These projects bring together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. The outstanding biomedical research at the University of Dundee was recognised by its high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.

Eligibility: Applications for these MRC studentships are invited from excellent UK* students expected to hold (or be about to achieve) at least a 2:1 Honours degree in a relevant subject.
*Some EU students may be eligible for a full award if you meet Research Council residency criteria and other exceptions may apply.