Kinases and DNA damage

Proper regulation and control of the DNA damage response is needed to suppress alterations in the genome that may result in cancer. A group of proteins known to play an important role in the DNA damage response is kinases. Indeed, many kinases are mutated in a variety of human cancers. However, when taken as a whole, it is apparent that the large majority of kinases are understudied. We established and performed an assay that allowed us to map which kinases are important in responding to DNA damage. We identified four kinases that are particularly interesting to study since they have been reported to play an important role in cancer. Hence the aim of this project is to better characterise and understand how these four kinases response to DNA damage, especially the types of DNA damage used as chemotherapy. We envisage that this research may lead to the better treatment of patients with cancer due to mutations in the identified kinases since paradoxically DNA damaging agents have been used as effective chemotherapeutic agents for several decades.

1. Artificial gene defect reveals target to fight genetic disease Fanconi anemia (FA). A rare, inherited disease, is caused by defective genes for DNA-repair in the cells of the patient leading to bone marrow failure, developmental abnormalities and increased cancer risk. Using genome-wide genetic approaches, researchers at CeMM systematically screened for the loss of an additional gene that could rescue the disease -and found it. The corresponding protein turned out to be a potential target that could be therapeutically exploited for FA. The study was published in Nature Communications (DOI: 10.1038/s41467-018-04649-z). 2. When two wrongs make a right: Artificial CRISPR gene disruptions could rescue genetic disease. Defective DNA repair mechanisms can lead to diseases like Fanconi anemia. Utilizing a concept called "synthetic viability", researchers at CeMM, in international collaboration, found additional gene disruptions that rescue the phenotype of this disease in cell culture and identified the responsible protein complex. The study, published in Nature Communications, intriguingly demonstrates the potential of synthetic viability screens to identify genetic interactions rescuing cells with defects in the DNA damage response (DOI: 10.1038/s41467-017-01439-x). 3. Tracing the footprints of a tumor: genomic "scars" allow cancer profiling. DNA mutations driving cancer development are caused by different mechanisms, each of them leaving behind specific patterns, or "scars" in the genome. In principle, the combination of those scars, so-called mutational signatures, allow for profiling of the cancer type and its development - but the noisy environment of a cancer genome, makes correlations at times difficult. Using CRISPR-Cas9 technology, researchers at CeMM and the Wellcome Trust Sanger Institute at Cambridge, UK were able to show for the first time in cell culture that specific genetic alterations indeed lead to the predicted pattern of mutational signaturesobserved in human cancers. The results were published in Nature Communications (DOI: 10.1038/s41467-018-04052-8). 4. Diabetes drug helps repair UV-damaged DNA in cells of "Moon children". The severe and debilitating genetic disease Xeroderma pigmentosum impedes cells to repair UV-induced DNA damage. Scientists from CeMM found a drug approved for diabetes treatment to alleviate the impact of the gene defect in cell culture, which led to the discovery of a previously unknown DNA repair mechanism. The study was published in Molecular Cell (DOI: 10.1016/j.molcel.2017.10.021).