A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrom e. The phenotype includes developmental defects, bone marrow failure, and c ell cycle abnormalities. At least eight complementation groups (A-H) exist, and although three of the corresponding complementation group genes have b een cloned, they lack recognizable motifs, and their functions are unknown. We have isolated a binding partner for the Fanconi anemia group C protein (FANCC) by yeast two-hybrid screening. We show that the novel gene, FAZF, e ncodes a 486 amino acid protein containing a conserved amino terminal BTB/P OZ protein interaction domain and three C-terminal Kruppel-like zinc finger s. FAZF is homologous to the promyelocytic leukemia zinc finger (PLZF) prot ein, which has been shown to act as a transcriptional repressor by recruitm ent of nuclear corepressors (N-CoR, Sin3. and HDAC1 complex). Consistent wi th a role in FA, BTB/POZ-containing proteins have been implicated in oncoge nesis, limb morphogenesis, hematopoiesis. and proliferation. We show that F AZF is a transcriptional repressor that is able to bind to the same DNA tar get sequences as PLZF. Our data suggest that the FAZF/FANCC interaction map s to a region of FANCC deleted in FA patients with a severe disease phenoty pe. We also show that FAZF and wild-type FANCC can colocalize in nuclear fo ci, whereas a patient-derived mutant FANCC that is compromised for nuclear localization cannot. These results suggest that the function of FANCC may b e linked to a transcriptional repression pathway involved in chromatin remo deling. (C) 1999 by The American Society of Hematology.