Jesper Svejstrup


Multi-omic analysis of the transcription-related DNA damage response

The Mechanisms of Transcription laboratory is interested in the cellular mechanisms that ensure genome stability, particularly in active genes. Over the last couple of years, it has thus become clear that gene expression comes at a cost, namely increased genome instability. In general, the interface between transcription and other DNA-related processes - such as chromatin remodeling, DNA replication, and DNA repair, is an area we are very active in. Indeed, it is fair to say that we are among the world leaders in this subject area. Research in the subject has recently gained a lot of attention because of its relevance to human diseases, such as cancer and neurological disorders.

Interestingly, while transcription can itself lead to genome instability, cells also have to contend with the situation where the transcribing polymerase runs into DNA lesions, such as those generated by chemicals or UV-light. When such damage occurs in the transcribed strand, it results in an absolute block to further transcript elongation. Fortunately, cells have evolved mechanisms to deal with this problem. First of all, transcription-stalling DNA damage somehow triggers a signalling pathway, which tells the cell to stop all transcription, even in genes that are not themselves damaged. This global DNA damage response is both fascinating and very poorly understood. We want to understand it, and this is one project that an incoming student might be interested in.

At the local level, the damage-stalled polymerase itself sends a signal that it has encountered DNA damage, which has to be dealt with quickly. Such repair, which is fast and directed only at active genes, is called transcription-coupled DNA repair. We know many of the factors involved, but the mechanism is still unclear, and there are certainly many proteins involved that we do not know about yet, and which we want to find. We are also working towards understanding some of the already known, key factors, such as the DNA translocase called Cockayne Syndrome B (CSB), and the ubiquitin-ligase component called CSA. As indicated from their names, these genes are mutated in a human disorder called Cockayne Syndrome, and we have over the last couple of years been interested in finding ways in which we can help CS patients through our work.

These are examples of the sorts of project that may be available in our research group. Only one studentship is available with this group and the precise project will be decided on consultation with the supervisor.  In general, we are studying basic biochemical mechanisms that are highly relevant for human disease. Indeed, although the lab started up as a yeast lab many years ago, we now work exclusively with human cells, using a variety of approaches, such as CRISPR gene knockout technology, biochemistry and proteomics, genomics, and the modern genome-wide approaches. This means that any student joining the lab will get an unusually broad education in multiple cutting-edge approaches, a great steppingstone for any future ambitions.

1. Williamson, L., Saponaro, M., Boeing, S., East, P., Mitter, R., Kantidakis, T., Kelly, G. P., Lobley, A., Walker, J., Spencer-Dene, B., Howell, M., Stewart, A. and Svejstrup, J. Q. (2017)
UV irradiation induces a non-coding RNA that functionally opposes the protein encoded by the same gene.
Cell 168: 843-855. PubMed abstract

2. Boeing, S., Williamson, L., Encheva, V., Gori, I., Saunders, R. E., Instrell, R., Aygün, O., Rodriguez-Martinez, M., Weems, J. C., Kelly, G. P., Conaway, J. W., Conaway, R. C., Stewart, A., Howell, M., Snijders, A. P. and Svejstrup, J. Q. (2016)
Multiomic analysis of the UV-induced DNA damage response.
Cell Reports  15: 1597-1610. PubMed abstract

3. Wang, Y., Jones-Tabah, J., Chakravarty, P., Stewart, A., Muotri, A., Laposa, R. R. and Svejstrup, J. Q. (2016)
Pharmacological bypass of Cockayne syndrome B function in neuronal differentiation.
Cell Reports  14: 2554-2561. PubMed abstract

4. Kantidakis, T., Saponaro, M., Mitter, R., Horswell, S., Kranz, A., Boeing, S., Aygün, O., Kelly, G. P., Matthews, N., Stewart, A., Stewart, A. F. and Svejstrup, J. Q. (2016)
Mutation of cancer driver MLL2 results in transcription stress and genome instability.
Genes & Development 30: 408-420.> PubMed abstract

5. Saponaro, M., Kantidakis, T., Mitter, R., Kelly, G. P., Heron, M., Williams, H., Söding, J., Stewart, A. and Svejstrup, J. Q. (2014)
RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress.
Cell  157: 1037-1049. PubMed abstract