Maintenance of genome stability is essential for the healthy development of an organism, for tissue and cell homeostasis, and for fertility. However, DNA is constantly subjected to internal and external factors that challenge its integrity. Therefore, cells are equipped with DNA repair mechanisms that deal with different types of DNA lesions, including DNA double strand breaks (DSBs). Defects in these repair mechanisms cause a plethora of human syndromes, including increased risk of cancer 1. On the other hand, cancerous cells often contain mutations that down regulate specific DNA repair pathways, making these cells reliant on the remaining repair mechanisms. This represents a vulnerability of cancerous cells that can be exploited by developing inhibitors targeting specific DNA repair pathways. Accurate DNA repair is also essential for fertility as it plays a key role during meiosis, the specialised cell division programme that creates haploid gametes from diploid germ cells. Recent studies show that some meiosis-specific proteins also provide DNA damage in cancer cells, making them potential therapeutical targets. The main goal of this project is to develop inhibitors against one such protein, HORMAD1.
Proteins containing a HORMA-domain are key components of the DNA repair machinery in both somatic (REV7) and meiotic cells (HORMAD1)2. These proteins are characterised by the presence of two different folding configurations: an “open” inactive configuration and a “closed” conformation in which the “safety belt” of the HORMA domain is reorganised to topologically entrap a short “closure motif” peptide from an interactor, forming active protein complexes3. HORMAD1 is overexpressed in many cancer cells and recent reports show that it promotes homologous recombination and radioresistance in malignant cells 4, 5. How HORMAD1 contributes to DNA repair in cancer cell is not understood. By developing inhibitors that lock HORMAD1 in a closed conformation, we hope to block its contribution to DNA repair in cancer cells and to elucidate the mechanisms by which HORMAD1 promotes DNA repair in cancer cells and during meiosis. This knowledge will also facilitate the development of inhibitors against other HORMADs, including REV7.
This interdisciplinary project will involve design and synthesis of HORMAD1 inhibitors (based on a known HORMAD1-binding domain) and functional in vivo and in vitro approaches to the test the efficiency of these inhibitors. In vitro approaches will include single-molecule imaging methods to measure the activity of HORMAD proteins.
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