Funding outcome

Fanconi Anemia is a rare recessive genetic disease, which means that affected children inherited from each parent a defect (mutation) in the same Fanconi Anemia gene. The parents, who have only one of the two gene copies defective, likely have no symptoms at all and are unaware of being mutation carriers. Fanconi Anemia children often display developmental birth defects, such as abnormal organs, bone problems, extra or missing thumbs, and aberrant skin pigmentation. The main characteristic of Fanconi Anemia though is a progressive bone marrow failure, leading to the inability to produce blood cells. Fanconi Anemia patients also have a very high risk of developing cancers. 21 genes have so far been identified to cause Fanconi Anemia, if mutated. All of them code for proteins that are involved in DNA repair, particular in fixing the dangerous linking of the two DNA strands by chemicals. Such chemicals could be chemotherapeutics used to kill cancer cells, but also byproducts of normal cell metabolism. The linking of the two strands is detrimental for any machinery that tries to read the DNA (and needs to 'unzip' it), whether to make copies of the DNA before cell division or to get the instructions for synthesizing proteins. These links are also very complicated to repair and, although we now know 21 proteins involved, not all the genes have been identified so far, as there are patients that do not have defects in any of the known 21 genes. We will study the most recently identified Fanconi Anemia gene, FANC V (The genes are named FANC A to FANC V). While it is known that deletion of FANC V leads to instability of the genetic material when challenged with DNA linking chemicals, the mechanism for this are yet to be uncovered. We will use a special type of microscopy allowing us to observe the FANC V protein (that we fused to a fluorescent protein) in the cell before and after damaging the DNA. We also study how this happens at the molecular level by dissecting signaling mechanisms and identifying proteins that partner with FANC V do remove the links. Knowing the mechanism underlying Fanconi Anemia is of great relevance for the patients. Over the last decades bone marrow transplants have greatly increased the life span for affected children, although the fact that the cells are from a different person still represent a big problem. Recently the first trials were initiated to correct the genes in their own bone marrow. Only the knowledge of the gene defect made this possible. Identifying partners of FANC V could allow clinicians to test whether these proteins are defective in Fanconi patients and ultimately lead to new therapies and markers for genetic counseling.