Human Molecular Genetics, 2000, Vol. 9, No. 18 2665-2674
© 2000 Oxford University Press
The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG
Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands, 1Department of Pathology and 2Department of Oncology, Free University Medical Center, NL-1081 HV Amsterdam, The Netherlands and 3Division of Molecular Medicine, Oregon Health Sciences University, Portland, OR 97201, USA
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.
+ To whom correspondence should be addressed. Tel: +31 20 444 8270; Fax: +31 20 444 8285; Email: h.joenje.humgen@med.vu.nl
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