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 cycle arrest, and chromosomal aberrations induced by DNA cross-linking agents, such as mitomycin C (MMC) and nitrogen mustard (HN2). Although MMC hypersensitivity is complemented in a subset of FA cells (complementation group C [FA-C]) by wild-type FAC cDNA, the cytoprotective mechanism is unknown. In the current study, we tested the hypothesis that FAC protein functions in the suppression of DNA interstand cross-link (ISC)-induced cell cycle arrest and apoptosis. Comparison of HN2-induced 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. Overexpression of wild-type FAC cDNA in FA-C lymphoblasts (HSC536N cell line) prevented HN2-induced growth inhibition, G2 arrest, and DNA fragmentation that is characteristic of apoptosis. In contrast cytoprotection was not conferred against the effects of the non-cross-linking mustards. Our data show that DNA ISCs induce apoptosis more potently than do DNA monoadducts and suggest that FAC suppresses specifically DNA ISC-induced apoptosis in the G2 phase of the cell cycle.
Marathi
U K
UK
Department of Molecular Pharmacology, St Jude Children's Research Hospital Memphis, TN 38101, USA.
Howell
S R
SR
Ashmun
R A
RA
Brent
T P
TP
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006131:Growth Inhibitors; D006801:Humans; D008466:Mechlorethamine / Q000037:antagonists & inhibitors / Q000737:chemistry; D016685:Mitomycin / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins; D011506:Proteins / Q000502:physiology*; D013329:Structure-Activity Relationship
D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006131:Growth Inhibitors; D009687:Nuclear Proteins; D011506:Proteins; D008466:Mechlorethamine; D016685:Mitomycin