title: A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201, USA. hoatlinm@OHSU.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Hoatlin
authors.forename: Y
authors.initials: Y
authors.lastname: Zhi
authors.forename: H
authors.initials: H
authors.lastname: Ball
authors.forename: K
authors.initials: K
authors.lastname: Silvey
authors.forename: A
authors.initials: A
authors.lastname: Melnick
authors.forename: S
authors.initials: S
authors.lastname: Stone
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.forename: N
authors.initials: N
authors.lastname: Hawe
authors.forename: G
authors.initials: G
authors.lastname: Owen
authors.forename: A
authors.initials: A
authors.lastname: Zelent
authors.forename: J D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C402243:ABTB1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C092037:ZBTB16 protein, human