The fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG

• Published in: Human molecular genetics 2000-11, Vol.9 (18), p.2665-2674
• Main Authors: DE WINTER, Johan P, VAN DER WEEL, Laura, DE GROOT, Jan, STONE, Stacie, WAISFISZ, Quinten, ARWERT, Fré, SCHEPER, Rik J, KRUYT, Frank A. E, HOATLIN, Maureen E, JOENJE, Hans
• Format: Article
• Language: English
• Subjects: Anemias. Hemoglobinopathies; Antibody Specificity; Biological and medical sciences; Blotting, Western; Cell Cycle Proteins; Cell Nucleus - chemistry; Cell Nucleus - metabolism; Cytoplasm - chemistry; Cytoplasm - metabolism; Diseases of red blood cells; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; FANCA protein; FANCC protein; FANCF protein; FANCG protein; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi Anemia Complementation Group A Protein; Fanconi Anemia Complementation Group C Protein; Fanconi Anemia Complementation Group F Protein; Fanconi Anemia Complementation Group G Protein; Fanconi Anemia Complementation Group Proteins; Genetic Complementation Test; Hematologic and hematopoietic diseases; Humans; Lymphocytes - metabolism; Lymphocytes - pathology; Macromolecular Substances; Medical sciences; Models, Biological; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Precipitin Tests; Protein Binding; Protein Biosynthesis; Proteins - genetics; Proteins - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.18.2665

Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and squamous cell carcinoma. At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents. Complementation analysis has indicated that at least seven distinct genes are involved in the pathogenesis of FA. Despite the identification of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of the 'FA pathway' has remained enigmatic, as the FA proteins lack sequence homologies or motifs that could point to a molecular function. To further define this pathway, we studied the subcellular localizations and mutual interactions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA complementation groups. This implies that each of the FA proteins, except FANCD, is required for these complexes to form. Similarly, we show that the interaction between FANCA and FANCC is restricted to wild-type and FA-D cells. Furthermore, we document the subcellular localization of FANCA and the FANCA/FANCG complex in all FA complementation groups. Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity.