title: Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein.
abstract: t(12;21) is the most frequent translocation found in pediatric B-cell acute lymphoblastic leukemias. This translocation fuses a putative repressor domain from the TEL DNA-binding protein to nearly all of the AML-1B transcription factor. Here, we demonstrate that fusion of the TEL pointed domain to the GAL4 DNA-binding domain resulted in sequence-specific transcriptional repression, indicating that the pointed domain is a portable repression motif. The TEL pointed domain functioned equally well when the GAL4 DNA-binding sites were moved 600 bp from the promoter, suggesting an active mechanism of repression. This lead us to demonstrate that wild-type TEL and the t(12;21) fusion protein bind the mSin3A corepressor. In the fusion protein, both TEL and AML-1B contribute mSin3 interaction domains. Deletion mutagenesis indicated that both the TEL and AML-1B mSin3-binding domains contribute to repression by the fusion protein. While both TEL and AML-1B associate with mSin3A, TEL/AML-1B appears to bind this corepressor much more stably than either wild-type protein, suggesting a mode of action for the t(12;21) fusion protein.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fenrick
authors.forename: J M
authors.initials: JM
authors.lastname: Amann
authors.forename: B
authors.initials: B
authors.lastname: Lutterbach
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J J
authors.initials: JJ
authors.lastname: Westendorf
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
authors.forename: S W
authors.initials: SW
authors.lastname: Hiebert
mesh_terms: D002051:Burkitt Lymphoma / Q000235:genetics; D002648:Child; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; C099683:SIN3A transcription factor; C102421:TEL-AML1 fusion protein