Cloning and analysis of the murine Fanconi anemia group C cDNA

Fanconi anemia (FA) is one of a group of disorders characterizedat the cellular level by a combination of hypersensitivity toDNA-damaging agents, chromosomal instability, and defectiveDNA repair. Clinical features of FA include pancytopenia, oftenaccompanied by specific congenital malformations, and a predispositionto leukemia. Since the hematological manifestations are thecritical defect in terms of prognosis, FA is a candidate diseasefor gene replacement therapy, and the development of a mousemodel system is essential for the initial stages of this work.Previously, we have cloned the gene defective in FA group Cby complementation of the intrinsic sensitivity of FA cellsto DNA cross-linking agents. We have now cloned the murine homologueof the human FACC cDNA. The mouse cDNA (Facc) shares 79% aminoacid sequence similarity with the human gene product. The expressionof the mouse cDNA in human FA(C) cells restores the cellulardrug sensitivity to normal levels. Thus, the function of theprotein has been conserved despite the significant sequencedivergence. PCR analysis of mouse tissue RNA reveals that thegene is expressed in all adult tissues, while in situ RNA hybridizationexperiments show tissue specific expression at late stages offetal development. Cross-hybridizing sequences exist in DNAfrom other mammals, chicken and Drosophila. These results supportthe hypothesis that the FACC gene product has a role in a basicaspect of cellular protection against DNA damaging agents andthat this function has been conserved during evolution.