Molecular modeling of wtp53-DNA interactions suggest a potential influence of amino acid R283 on sequence-specific binding of K120 to p53 responsive elements (p53RE). The distances between K120 and the first two 5` nucleotides of the p53RE present in the genes for CDKN1A (5`-GAACATGTCC-cAACATGTTG-3`) and BAX (5`-tcACAAGTTa-AGACAAGCCT-3`) are shown in white and green, respectively. The substitution of purines (G,A) by pyrimidines (t,c) in the BAX p53RE results in Van der Waals overlaps. The distance between the &bgr;-carbon of K120 to the bases is reduced from 6.08 Å (G) to 3.27 Å (t) and the distance between the &zgr;-nitrogen of K120 and the bases is reduced from 2.3 Å (A) to 1.68 Å (c). This model predicts that the p53RE of the BAX promoter (and possibly other promoters with a p53RE with 5` Py substitutions) will bind p53 with a lower affinity than the p53RE of the CDKN1A promoter. Adjacent amino acid R283 may serve to stabilize K120 in the correct orientation for sequence-specific interaction with DNA. This interaction is disrupted by a R283H substitution, a mutation that when present in the germline is able to initiate human astrocytoma. For details, see the article by Fulci et al. on page 2897 of this issue.