Abstract |
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.
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Authors | M E Hoatlin, Y Zhi, H Ball, K Silvey, A Melnick, S Stone, S Arai, N Hawe, G Owen, A Zelent, J D Licht |
Journal | Blood
(Blood)
Vol. 94
Issue 11
Pg. 3737-47
(Dec 01 1999)
ISSN: 0006-4971 [Print] United States |
PMID | 10572087
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- ABTB1 protein, human
- Cell Cycle Proteins
- DNA-Binding Proteins
- FANCC protein, human
- Fanconi Anemia Complementation Group C Protein
- Fanconi Anemia Complementation Group Proteins
- Kruppel-Like Transcription Factors
- Nuclear Proteins
- Promyelocytic Leukemia Zinc Finger Protein
- Proteins
- Repressor Proteins
- Transcription Factors
- ZBTB16 protein, human
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Topics |
- Amino Acid Sequence
- Base Sequence
- Cell Cycle Proteins
- DNA-Binding Proteins
(genetics, metabolism)
- Fanconi Anemia
(genetics, metabolism)
- Fanconi Anemia Complementation Group C Protein
- Fanconi Anemia Complementation Group Proteins
- Gene Expression Regulation
- Humans
- Kruppel-Like Transcription Factors
- Molecular Sequence Data
- Nuclear Proteins
- Promyelocytic Leukemia Zinc Finger Protein
- Proteins
(genetics, metabolism)
- Repressor Proteins
(genetics, metabolism)
- Transcription Factors
(genetics, metabolism)
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