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The Fanconi Anemia Group C Gene Product Is Located in Both the
Nucleus and Cytoplasm of Human Cells
Maureen E. Hoatlin,
Tracy A. Christianson,
Winnie W. Keeble,
Adam
T. Hammond,
Yu Zhi,
Michael C. Heinrich,
Paula A. Tower, and
Grover
C. Bagby Jr
From the Division of Hematology and Medical Oncology,
Oregon Health Sciences University, Portland; and The Portland Veterans
Administration Medical Center, Portland, OR.
The Fanconi anemia (FA) complementation group C (FAC) protein gene
encodes a cytoplasmic protein with a predicted Mr
of 63,000. The protein's function is unknown, but it has been
hypothesized that it either mediates resistance to DNA cross-linking
agents or facilitates repair after exposure to such factors. The
protein also plays a permissive role in the growth of colony-forming
unit-granulocyte/macrophage (CFU-GM), burst-forming unit-erythroid
(BFU-E), and CFU-erythroid (CFU-E). Attributing a specific function to
this protein requires an understanding of its intracellular location.
Recognizing that prior study has established the functional importance
of its cytoplasmic location, we tested the hypothesis that FAC protein
can also be found in the nucleus. Purified recombinant Escherichia
coli-derived FAC antigens were used to create antisera able to
specifically identify an Mr = 58,000 protein in lysates from human Epstein-Barr virus (EBV)-transformed cell
lines by immunoblot analysis. Subcellular fractionation of the cell
lysates followed by immunoblot analysis revealed that the majority of
the FAC protein was cytoplasmic, as reported previously; however,
approximately 10% of FAC protein was reproducibly detected
in nuclear fractions. These results were reproducible by two different
fractionation methods, and included markers to control for
contamination of nuclear fractions by cytoplasmic proteins. Moreover,
confocal image analysis of human 293 cells engineered to express FAC
clearly demonstrated that FAC protein is located in both cytoplasmic
and nuclear compartments, consistent with data obtained from
fractionation of the FA cell lines. Finally, complementation of the FAC
defect using retroviral-mediated gene transfer resulted in a
substantial increase in nuclear FAC protein. Therefore, while
cytoplasmic localization of this protein appears to be functionally
important, it may also exert some essential nuclear function.
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1418-1425
© 1998 by The American Society of Hematology.
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