Towards targeting the Cohesin network in Cancer therapy, utilizing its fundamental roles in DNA damage response and repair

For our long-term goal to identify new targets for cancer treatment we focus on the protein complex Cohesin, which holds the sister chromatids together until anaphase, a function essential for correct chromosome segregation called ´cohesion´. Cohesin is also essential for DNA repair, genome structure and gene expression.

Mutations in Cohesin or its regulators are frequently found in malignancies such as leukemias, sarcomas, breast and prostate cancer.

The reason for this is not clear, although Cohesin has been found to prevent aberrant translocations between distal DNA double strand breaks (DSBs), a frequent cause for tumour development, and chromosome missegregation, known to drive childhood leukemias.

We aim at unravelling the mechanism for Cohesin, and its loader NIPBL in DNA damage response and repair and will investigate the connection between Cohesin loading, chromatin structure and transcription at DSB. We will also study the correlation between the Cohesin network and telomere maintenance.

We utilize budding yeast and human immortalised or cancer cell lines, as model systems, and apply cell biology methods and yeast genetics, as well as biochemistry combined with mass spectrometry, Hi-C and selected sequencing methods.

We do this to know if and how inhibiting the Cohesin pathway will cause increased DNA damage sensitivity, thereby ultimately killing already DNA damage sensitive cancer cells. This would define the Cohesin network as a new target for Cancer drugs.