A Novel BTB/POZ Transcriptional Repressor Protein Interacts With the Fanconi Anemia Group C Protein and PLZF

• Published in: Blood Vol. 94; no. 11; pp. 3737 - 3747
• Main Authors: Hoatlin, Maureen E., Zhi, Yu, Ball, Helen, Silvey, Kirsten, Melnick, Ari, Stone, Stacie, Arai, Sally, Hawe, Nicola, Owen, Gareth, Zelent, Arthur, Licht, Jonathan D.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.12.1999; The Americain Society of Hematology
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; Cell Cycle Proteins; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi Anemia Complementation Group C Protein; Fanconi Anemia Complementation Group Proteins; Gene Expression Regulation; Humans; Kruppel-Like Transcription Factors; Medical genetics; Medical sciences; Molecular Sequence Data; Nuclear Proteins; Promyelocytic Leukemia Zinc Finger Protein; Proteins - genetics; Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Human; Chromosome fragility; Fanconi anemia; Transcription; Pathogenesis; Genetics; Genotype; Transcription repressor; Hemopathy; Mutation; Gene expression; Genetic disease
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.11.3737

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome. The phenotype includes developmental defects, bone marrow failure, and cell cycle abnormalities. At least eight complementation groups (A-H) exist, and although three of the corresponding complementation group genes have been 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, encodes a 486 amino acid protein containing a conserved amino terminal BTB/POZ protein interaction domain and three C-terminal Krüppel-like zinc fingers. FAZF is homologous to the promyelocytic leukemia zinc finger (PLZF) protein, which has been shown to act as a transcriptional repressor by recruitment of nuclear corepressors (N-CoR, Sin3, and HDAC1 complex). Consistent with a role in FA, BTB/POZ-containing proteins have been implicated in oncogenesis, limb morphogenesis, hematopoiesis, and proliferation. We show that FAZF is a transcriptional repressor that is able to bind to the same DNA target sequences as PLZF. Our data suggest that the FAZF/FANCC interaction maps to a region of FANCC deleted in FA patients with a severe disease phenotype. We also show that FAZF and wild-type FANCC can colocalize in nuclear foci, whereas a patient-derived mutant FANCC that is compromised for nuclear localization cannot. These results suggest that the function of FANCC may be linked to a transcriptional repression pathway involved in chromatin remodeling.