Induction of Fanconi anemia cellular phenotype in human 293 cells by overexpression of a mutant FAC allele

The Journal of Clinical Investigation
H YoussoufianM Buchwald

Abstract

The polypeptide encoded by the Fanconi anemia (FA) complementation group C gene, FAC, binds to a group of cytoplasmic proteins in vitro and may form a multimeric complex. A known mutant allele of FAC resulting from the substitution of Pro for Leu at codon 554 fails to correct the sensitivity of FA group C cells to mitomycin C. We reasoned that overexpression of the mutant protein in a wild-type cellular background might induce the FA phenotype by competing with endogenous FAC for binding to the accessory proteins. After stable transfection of 293 cells with wild-type and a mutant FAC allele containing the L554P substitution, four independent clones that expressed four-to-fifteen fold higher levels of transcript from the mutant transgene relative to the endogenous FAC gene showed hypersensitivity to mitomycin C. By contrast, both parental and FAC-overexpressing cells maintained their relative resistance to mitomycin C. No differences in the biosynthesis, subcellular localization and protein interactions of the normal and mutant proteins were detected. The induction of the FA phenotype in this system is compatible with the competition hypothesis and provides support for a functional role of the FAC-binding proteins in vivo.

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Citations

Jun 5, 1998·Molecular Medicine Today·M Carreau, M Buchwald
Dec 17, 1997·Nature Genetics·G M KupferA D D'Andrea
Nov 10, 2001·Annual Review of Genomics and Human Genetics·R E Moses
Jan 27, 1998·Hematology/oncology Clinics of North America·G M KupferA D D'Andrea
Oct 4, 2002·The Journal of Biological Chemistry·Sarah L Donahue, Colin Campbell
May 16, 2003·The Journal of Biological Chemistry·Sarah L DonahueColin Campbell

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