Abstract
Fanconi anemia (FA) is a genomic instability disorder, clinically characterized by congenital abnormalities, progressive bone marrow failure, and predisposition to malignancy. Cells derived from patients with FA display a marked sensitivity to DNA cross-linking agents, such as mitomycin C (MMC). This observation has led to the hypothesis that the proteins defective in FA are involved in the sensing or repair of interstrand cross-link lesions of the DNA. A nuclear complex consisting of a majority of the FA proteins plays a crucial role in this process and is required for the monoubiquitination of a downstream target, FANCD2. Two new FA genes, FANCB and FANCL, have recently been identified, and their discovery has allowed a more detailed study into the molecular architecture of the FA pathway. We demonstrate a direct interaction between FANCB and FANCL and that a complex of these proteins binds FANCA. The interaction between FANCA and FANCL is dependent on FANCB, FANCG, and FANCM, but independent of FANCC, FANCE, and FANCF. These findings provide a framework for the protein interactions that occur "upstream" in the FA pathway and suggest that besides the FA core complex different subcomplexes exist that may have specific functions other than the monoubiquitination of FANCD2.
Publication types
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Line
-
Fanconi Anemia / etiology
-
Fanconi Anemia / genetics
-
Fanconi Anemia / metabolism*
-
Fanconi Anemia Complementation Group A Protein / chemistry
-
Fanconi Anemia Complementation Group A Protein / genetics
-
Fanconi Anemia Complementation Group A Protein / metabolism
-
Fanconi Anemia Complementation Group G Protein / chemistry
-
Fanconi Anemia Complementation Group G Protein / genetics
-
Fanconi Anemia Complementation Group G Protein / metabolism
-
Fanconi Anemia Complementation Group L Protein / chemistry
-
Fanconi Anemia Complementation Group L Protein / genetics
-
Fanconi Anemia Complementation Group L Protein / metabolism
-
Fanconi Anemia Complementation Group Proteins / chemistry
-
Fanconi Anemia Complementation Group Proteins / genetics
-
Fanconi Anemia Complementation Group Proteins / metabolism*
-
Humans
-
In Vitro Techniques
-
Models, Molecular
-
Multiprotein Complexes
-
Mutation, Missense
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Transfection
Substances
-
FANCA protein, human
-
FANCG protein, human
-
Fanconi Anemia Complementation Group A Protein
-
Fanconi Anemia Complementation Group G Protein
-
Fanconi Anemia Complementation Group Proteins
-
Multiprotein Complexes
-
Recombinant Proteins
-
FANCL protein, human
-
Fanconi Anemia Complementation Group L Protein