| Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by genomic instability and a heightened risk of malignancy. Seven of the FA gene products associate in a core nuclear complex, are required for activation of FANCD2 by monoubiquitination, and are thought to be functionally epistatic. The extreme sensitivity of FA cells to DNA damaging agents suggest that the FA proteins have cellular roles in DNA repair and/or cell cycle control. Our group has recently found that activation of FANCD2 by the nuclear complex proteins is required for activation of the radiation induced G2/M checkpoint. I established that FANCG is an in vitro and in vivo phosphorylation substrate of Chk2, a major regulator of G2/M checkpoint control. Further, mutation of a single amino acid, serine 426, was sufficient to confer the characteristic mitomycin c and ionizing radiation hypersensitivity of Fancg deficient primary myeloid progenitor cells and immortalized FANCG mutant cell lines. Surprisingly, FANCD2 monoubiquitination was normal. These data support the hypothesis that FANCG has both FANCD2 dependent and independent functions in maintaining genomic stability. To understand the role of FANCG alone and in cooperation with other FA core nuclear complex proteins in the development of bone marrow failure and leukemia, knockout mice containing disruptions of Fancg, Fancc or both loci were employed. The data show that loss of Fancg or Fancc only results in a significant reduction of clonogenic stem/progenitor cells and long term repopulating stem cells. Further, mice containing genetic disruptions of both Fancc and Fancg develop malignancies, whereas mice with a disruption at either locus alone do not. These data demonstrate that Fancc and Fancg have distinct functions in hematopoiesis and in maintaining genomic stability. Taken together, these data confirm by biochemical analyses and genetic models that FANCG has a unique role that is not epistatic with the FA core nuclear complex. |
