A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA.
Fanconi anemia (FA) is a recessively inherited disease characterized at the cellular level by spontaneous chromosomal instability and specific hypersensitivity to cross-linking agents. FA is genetically heterogeneous, comprising at least eight complementation groups (A-H). We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes to the cytoplasm and nucleus of the cell and assembles in a molecular complex with the FANCA protein, both in vivo and in vitro. Endogenous FANCA/FANCG complex was detected in both non-FA cells and in FA cells from groups D and E. By contrast, no complex was detected in specific cell lines belonging to groups A and G, whereas reduced levels were found in cells from groups B, C, F, and H. Wild-type levels of FANCA/FANCG complex were restored upon correction of the cellular phenotype by transfection or cell fusion experiments, suggesting that this complex is of functional significance in the FA pathway. These results indicate that the cellular FA phenotype can be connected to three biochemical subtypes based on the levels of FANCA/FANCG complex. Disruption of the complex may provide an experimental strategy for chemosensitization of neoplastic cells.
Waisfisz
Q
Q
Department of Clinical Genetics and Human Genetics, Free University, NL-1081 BT, Amsterdam, The Netherlands.
de Winter
J P
JP
Kruyt
F A
FA
de Groot
J
J
van der Weel
L
L
Dijkmans
L M
LM
Zhi
Y
Y
Arwert
F
F
Scheper
R J
RJ
Youssoufian
H
H
Hoatlin
M E
ME
Joenje
H
H
D002459:Cell Fusion; D002460:Cell Line; D002873:Chromosome Fragility; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics*; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; D005816:Genetic Complementation Test; D006801:Humans; D008214:Lymphocytes; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C499909:FANCG protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; D011506:Proteins; D011993:Recombinant Fusion Proteins