Untersuchung der Rolle von Fanconi Anämie Protein A im Rahmen des Netzwerkes von "Caretaker"-Genen
Final Report Abstract
The purpose of my research in the laboratory of Dr. M. E. Hoatlin was to study the role of FANCA in the network of caretaker genes. During my fellowship exiting findings changed the view of the Fanconi Anemia research. It became clear that several genetically inherited diseases are connected on a molecular level in the form of multiprotein complexes that form in response to DNA damage. Proteins mutated in Fanconi Anemia, Bloom syndrome and genetically inherited breast cancer are interacting in different DNA repair pathways. It also became clear that an important protein connecting these pathways is FANCD2, which acts downstream of the core complex with FANCA. In addition a new FA protein FANCL was cloned and characterized with participation of our laboratory. Therefore the emphasis of my research focused on the role of FANCD2 and FANCL at the intersections with Bloom syndrome and BRCA1 pathways. Major findings of my fellowship research were 1) FANCA foci formation is dependent on the cell cycle phase; 2) FANCA foci partially co‐localize with FANCL, FANCD2 and Blm; 3) FANCL is required for foci formation of FANCD2 in response to DNA interstrand crosslinks; 4) FANCD2 foci formation in response to DNA interstrand crosslinks is independent of BRCA1. The manuscript “A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome” was awarded the “Appreciation Award of the Fanconi Anemia Research Fund” at the 2003 annual meeting for publication of the year. The FANCD2 antibody I generated was licensed to a company by OHSU and my contributions were honored with the “Technology Innovation Award” from OHSU in 2005. The findings that the molecular pathways of several genetically inherited diseases that fail to repair DNA damage are interconnected changed the field of Fanconi Anemia research significantly. It resulted in new collaborations with researchers from the Bloom syndrome and breast cancer research field, new interest in FA research as a model for cancer research and DNA repair diseases, and increased funding opportunities for FA research through others agencies.
Publications
- (2003). A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol. Cell Biol. 23, 3417‐3426
Meetei,A.R., Sechi,S., Wallisch,M., Yang,D., Young,M.K., Joenje,H., Hoatlin,M.E., and Wang,W.
- (2003). A novel ubiquitin ligase is deficient in Fanconi anemia. Nat. Genet. 35, 165‐170
Meetei,A.R., de Winter,J.P., Medhurst,A.L., Wallisch,M., Waisfisz,Q., van,d., V, Oostra,A.B., Yan,Z., Ling,C., Bishop,C.E., Hoatlin,M.E., Joenje,H., and Wang,W.
- (2003). FANCD2 protein is expressed in proliferating cells of human tissues that are cancer‐ prone in Fanconi anaemia. J. Pathol. 201, 198‐203
Holzel,M., van Diest,P.J., Bier,P., Wallisch,M., Hoatlin,M.E., Joenje,H., and de Winter,J.P.
- (2006). Fanconi anemia proteins are required to prevent accumulation of replication‐associated DNA double‐strand breaks. Mol. Cell Biol. 26, 425‐437
Sobeck,A., Stone,S., Costanzo,V., de Graaf,B., Reuter,T., de Winter,J., Wallisch,M., Akkari,Y., Olson,S., Wang,W., Joenje,H., Christian,J.L., Lupardus,P.J., Cimprich,K.A., Gautier,J., and Hoatlin,M.E.
