Uncovering function and mode of activation of the central Fanconi Anemia FANCD2/FANCI DNA repair protein complex, a potential cancer drug target.

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The human genome contains thousands of genes, activities of which are important for a functioning healthy human body. Our organism is made up of billions of cells, all originating from one single cell. This is possible, since that original cell divided into two cells, which subsequently produced four cells, and so on. It is of crucial importance that the entire genome is duplicated accurately during each division. The genome is constantly subjected to damage from a variety of sources from inside or outside the cell. If cells fail to maintain an intact genome,, mutations can arise, which can cause a number of severe diseases, such as cancer. To counter-act the effects of damage, our cells have evolved sophisticated mechanisms to protect DNA, so called DNA repair pathways. These pathways safeguard the genome to prevent harmful mutations from arising. When one of these pathways fails to function properly, it allows for mutations to arise unhindered. One particularly serious example of this is when the Fanconi Anemia DNA repair pathway is not operational. When that happens, it causes the disease Fanconi Anemia (FA). FA is a genetic disease characterized by various developmental defects and predisposition to cancer in patients. Many patients do not survive beyond their teenage years, underscoring the seriousness of the disease. So far, 18 FA proteins have been identified, which includes the BRCA1 and BRCA2 genes, which are mutated in breast cancer. Together, these proteins compose the FA pathway, which is responsible for repairing DNA crosslinks, a dangerous type of DNA damage. Mutation in any of the corresponding 18 genes can cause FA. At the same time, since these DNA crosslinks are so dangerous, drugs causing such crosslinks are used in the clinic to treat cancer in non-FA cancer patients. However, patients often develop resistance to these otherwise so successful drugs. It is believed that resistance is caused by an increased ability of the cancer cells to repair DNA crosslinks. If we could prevent the cancer cells from repairing the crosslinks, we could treat these deadly cancers and cure the patients. The aim of this proposal is to learn more about how cancer cells repair DNA crosslinks, so that we can use this information to design drugs that can treat patients with currently untreatable cancers. More specifically, we will study a protein complex called the FANCD2/FANCI complex. This complex is central and absolutely critical for cells to repair DNA crosslinks. We have recently discovered a novel domain, or part, of this complex, which is fundamental to its function. We are going to make use of this unique discovery to further our understanding of how the FANCD2/FANCI complex controls DNA crosslink repair. The increased understanding will in turn pave the way for the development of novel cancer drugs.