THE FANCONI-ANEMIA COMPLEMENTATION GROUP-C PROTEIN CORRECTS DNA INTERSTRAND CROSS-LINK-SPECIFIC APOPTOSIS IN HSC536N CELLS

Fanconi anemia (FA) cells are hypersensitive to cytotoxicity, cell cyc le arrest, and chromosomal aberrations induced by DNA cross-linking ag ents, such as mitomycin C (MMC) and nitrogen mustard (HN2). Although M MC hypersensitivity is complemented in a subset of FA cells (complemen tation group C [FA-C]) by wild-type FAC cDNA, the cytoprotective mecha nism is unknown. In the current study, we tested the hypothesis that F AC protein functions in the suppression of DNA Interstrand cross-link (ISC)-induced cell cycle arrest and apoptosis. Comparison of HN2-induc ed cell cycle arrest and apoptosis with those of its non-cross-linking analogs, diethylaminoethyl chloride and 2-dimethylaminoethyl chloride , delineated the DNA ISC specificity of FAC-mediated cytoprotection. O verexpression of wild-type FAC cDNA in FA-C lymphoblasts (HSC536N cell line) prevented HN2-induced growth inhibition, G2 arrest, and DNA fra gmentation that is characteristic of apoptosis. In contrast, cytoprote ction was not conferred against the effects of the non-cross-linking m ustards. Our data show that DNA ISCs induce apoptosis more potently th an do DNA monoadducts and suggest that FAC suppresses specifically DNA ISC-induced apoptosis in the 62 phase of the cell cycle. (C) 1996 by The American Society of Hematology.