The functional impairment of fanconi anemia pathway due to FANCA mutation or polymorphism *
Fanconi anemia（FA）is a rare hereditary disorder caused by mutations in the FA core complex components such as FANCA, and FANCD2, and other related genes. The FA core complex is an E3 ligase that mono-ubiquitinates FANCD2 protein upon DNA damage. Cells from FA patients are highly sensitive to killing by interstrand crosslinking agents such as mitomycin C（MMC）and cisplatin. Recently, mutations of FA genes have been detected in cancer patients unrelated to FA. However, the role of the FA mutation in cancer has not been fully assessed. In the present study, we expressed FANCA cDNA having either the patient-derived mutation or single nucleotide polymorphisms（SNPs）in FANCA-deficient DT40 cell line, and examined effects on cisplatin sensitivity, FANCD2 monoubiquitination, and FANCA focus formation. The cells carrying FANCA with the SNPs displayed incomplete complementation of cisplatin sensitivity, and mildly decreased FANCD2 monoubiquitination after treatment with MMC. However, these cells formed nuclear FANCA foci after treatment with MMC, similarly to the cells that expressed wild type FANCA, whereas FANCA with the FA patient-derived mutation formed no nuclear foci. These results suggest that FANCA SNPs found in cancer patients could cause genome instability due to partial loss of FA pathway, leading to carcinogenesis.(Accepted on October 10，2006)
