Fanconi anemia protein complex is a novel target of the IKK signalsome.
Fanconi anemia (FA), a genetic disorder predisposing to aplastic anemia and cancer, is characterized by hypersensitivity to DNA-damaging agents and oxidative stress. Five of the cloned FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG) appear to be involved in a common functional pathway that is required for the monoubiquitination of a sixth gene product, FANCD2. Here, we report that FANCA associates with the IkappaB kinase (IKK) signalsome via interaction with IKK2. Components of the FANCA complex undergo rapid, stimulus-dependent changes in phosphorylation, which are blocked by kinase-inactive IKK2 (IKK2 K > M). When exposed to mitomycin C, cells expressing IKK2 K > M develop a cell cycle abnormality characteristic of FA. Thus, FANCA may function to recruit IKK2, thus providing the cell a means of rapidly responding to stress.
Otsuki
Tetsuya
T
Hematology Branch, NHLBI Bldg., Bethesda, Maryland 20892, USA.
Young
David B
DB
Sasaki
Dennis T
DT
Pando
Matthew P
MP
Li
Jianwu
J
Manning
Anthony
A
Hoekstra
Merl
M
Hoatlin
Maureen E
ME
Mercurio
Frank
F
Liu
Johnson M
JM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D016195:G2 Phase / Q000502:physiology; D005822:Genetic Vectors; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007700:Kinetics; D016685:Mitomycin / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D016685:Mitomycin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human