The DNA-binding domain of human c-Abl tyrosine kinase promotes the interaction of a HMG chromosomal protein with DNA

The biological activity of the c-Abt protein is linked to its tyrosine kina se and DNA-binding activities, The protein, which plays a major role in the cell cycle response to DNA damage, interacts preferentially with sequences containing an AAC motif and exhibits a higher affinity for bent or bendabl e DNA, as is the case with high mobility group (HMG) proteins. We have comp ared the DNA-binding characteristics of the DNA-binding domain of human c-A bl and the HMG-D protein from Drosophila melanogaster, c-Abl binds tightly to circular DNA molecules and potentiates the interaction of DNA with HMG-D . In addition, we used a series of DNA molecules containing modified bases to determine how the exocyclic groups of DNA influence the binding of the t wo proteins. Interfering with the 2-amino group of purines affects the bind ing of the two proteins similarly. Adding a a-amino group to adenines restr icts the access of the proteins to the minor groove, whereas deleting this bulky substituent from guanines facilitates the protein-DNA interaction. In contrast, c-Abl and HMG-D respond very differently to deletion or addition of the 5-methyl group of pyrimidine bases in the major groove. Adding a me thyl group to cytosines favours the binding of c-Abl to DNA but inhibits th e binding of HMG-D, Conversely deleting the methyl group from thymines prom otes the interaction of the DNA with HMG-D but diminishes its interaction w ith c-Abl, The enhanced binding of c-Abl to DNA containing 5-methylcytosine residues may result from an increased propensity of the double helix to de nature locally coupled with a protein-induced reduction in the base stackin g interaction. The results show that c-Abl has unique DNA-binding propertie s, quite different from those of HMG-D, and suggest an additional role for the protein kinase.