PREFERRED SEQUENCES FOR DNA RECOGNITION BY THE TAL1 HELIX-LOOP-HELIX PROTEINS

Tumor-specific activation of the TAL1 gene is the most common genetic alteration seen in patients with T-cell acute lymphoblastic leukemia. The TAL1 gene products contain the basic helix-loop-helix (bHLH) domai n, a protein dimerization and DNA-binding motif common to several know n transcription factors. A binding-site selection procedure has now be en used to evaluate the DNA recognition properties of TAL1. These stud ies demonstrate that TAL1 polypeptides do not have intrinsic DNA-bindi ng activity, presumably because of their inability to form bHLH homodi mers. However, TAL1 readily interacts with any of the known class A bH LH proteins (E12, E47, E2-2, and HEB) to form heterodimers that bind D NA in a sequence-specific manner. The TAL1 heterodimers preferentially recognize a subset of E-box elements (CANNTG) that can be represented by the consensus sequence AACAGATGGT. This consensus is composed of h alf-sites for recognition by the participating class A bHLH polypeptid e (AACAG) and the TAL1 polypeptide (ATGGT). TAL1 heterodimers with DNA -binding activity are readily detected in nuclear extracts of Jurkat, a leukemic cell line derived from a patient with T-Cell acute lymphobl astic leukemia. Hence, TAL1 is likely to bind a regulate the transcrip tion of unique subset of subordinate target genes, some of which may m ediate the malignant function of TAL1 during T-cell leukemogenesis.