RUNX1-RUNX1 Homodimerization Modulates RUNX1 Activity and Function

• Published in: The Journal of biological chemistry Vol. 282; no. 18; pp. 13542 - 13551
• Main Authors: Li, Donglan, Sinha, Kislay K., Hay, Maher A., Rinaldi, Ciro R., Saunthararajah, Yogen, Nucifora, Giuseppina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Binding Sites - genetics; Cell Differentiation - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Dimerization; Gene Expression Regulation - genetics; HeLa Cells; Hematopoietic Stem Cells - metabolism; Humans; Leukemia - genetics; Leukemia - metabolism; Mice; NIH 3T3 Cells; Oncogene Proteins, Fusion; Point Mutation; Protein Binding - genetics; Protein Structure, Tertiary - genetics; Response Elements
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M700074200

RUNX1 (AML1, CBFα2, PEBP2αB) is a transcription factor essential for the establishment of the hematopoietic stem cell. It is generally thought that RUNX1 exists as a monomer that regulates hematopoietic differentiation by interacting with tissue-specific factors and its DNA consensus through its N terminus. RUNX1 is frequently altered in human leukemia by gene fusions or point mutations. In general, these alterations do not affect the N terminus of the protein, and it is unclear how they consistently lead to hematopoietic transformation and leukemia. Here we report that RUNX1 homodimerizes through a mechanism involving C terminus-C terminus interaction. This RUNX1-RUNX1 interaction regulates the activity of the protein in reporter gene assays and modulates its ability to induce hematopoietic differentiation of hematopoietic cell lines. The promoters of genes regulated by RUNX1 often contain multiple RUNX1 binding sites. This arrangement suggests that RUNX1 could homodimerize to bring and hold together distant chromatin sites and factors and that if the dimerization region is removed by gene fusions or is altered by point mutations, as observed in leukemia, the ability of RUNX1 to regulate differentiation could be impaired.