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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2229-2236
The Fanconi Anemia Proteins FAA and FAC Function in Different Cellular
Compartments to Protect Against Cross-Linking Agent Cytotoxicity
Frank A.E. Kruyt and
Hagop Youssoufian
From the Department of Molecular and Human Genetics and the
Department of Medicine, Baylor College of Medicine, One Baylor Plaza,
Houston, TX.
Fanconi anemia (FA) is an autosomal recessive disease characterized
by chromosomal instability, bone marrow failure, and a high risk of
developing malignancies. Although the disorder is genetically
heterogeneous, all FA cells are defined by their sensitivity to the
apoptosis-inducing effect of cross-linking agents, such as mitomycin C
(MMC). The cloned FA disease genes, FAC and FAA, encode
proteins with no homology to each other or to any known protein. We
generated a highly specific antibody against FAA and found the protein
in both the cytoplasm and nucleus of mammalian cells. By subcellular
fractionation, FAA is also associated with intracellular membranes. To
identify the subcellular compartment that is relevant for FAA activity,
we appended nuclear export and nuclear localization signals to the
carboxy terminus of FAA and enriched its localization in
either the cytoplasm or the nucleus. Nuclear localization of FAA was
both necessary and sufficient to correct MMC sensitivity in FA-A cells.
In addition, we found no evidence for an interaction between FAA and
FAC either in vivo or in vitro. Together with a previous finding that
FAC is active in the cytoplasm but not in the nucleus, our results
indicate that FAA and FAC function in separate subcellular
compartments. Thus, FAA and FAC, if functionally linked, are more
likely to be in a linear pathway rather than form a macromolecular
complex to protect against cross-linker cytotoxicity.
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