Fanconi anemia strikes early in utero.

摘要

In this issue of Blood, Tulpule and colleagues describe the use of lentiviral vectors to knock down FANCA and FANCD2 in hESC lines, which results in early hema-topoietic defects reminiscent of the human disease. Fanconi anemia (FA) is an autosomal recessive disorder characterized by bone marrow failure, birth defects, and a predisposition to malignancy. A plethora of new scientific information has clearly established that the 13 known FA gene products are involved in the regulation of DNA repair (reviewed in de Winter and Joenje). It is currently believed that 8 of the FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear complex that functions "upstream" in the pathway to enzy-matically monoubiquitinate a heterodimer pairing between FANCI and FANCD2 (referred to as the ID heterodimer). Following this biochemical activation, the ID heterodimer is targeted to nuclear foci that contain BRCA1,RAD51, and BRCA2/ FANCD1, which ultimately participate in homology-directed DNA repair. FANCD2, FANCI, and BRCA2/FANCD1 thus act "downstream" in the pathway from the core complex, and may have additional functions in maintaining genomic integrity as well. This view of the FA pathway certainly explains the hypersensitivity of patients' cells to DNA cross-linking agents, which still forms the basis for diagnosing FA.