DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

Abstract

Sequence-speci®c transactivation of target genes is one of the most important molecular properties of the tumor suppressor p53. Binding of p53 to its target DNAs is tightly regulated, with modi®cations in the carboxyterminal regulatory domain of the p53 protein playing an important role. In this study we examined the possible in¯uence of DNA structure on sequence-speci®c DNA binding by p53, by analysing its binding to p53 consensus elements adopting di erent conformations. We found that p53 has the ability to bind to consensus elements which are present in a double-helical form, as well as to consensus elements which are located within alternative non-B-DNA structures. The ability of a consensus element to adopt either one of these conformations is dependent on its sequence symmetry, and is strongly in¯uenced by its sequence environment. Our data suggest a model according to which the conformational status of the target DNA is an important determinant for sequence-speci®c DNA binding by p53. Modi®cations in the carboxy-terminal regulatory region of p53 possibly determine the preference of p53 for a given DNA conformation.

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

“…On the contrary, binding of p53 to some of such isoforms was inhibited by PAb421. We concluded that sequencespeci®c DNA binding of p53 can be modulated both by p53 protein conformation and by the conformation of its cognate DNA sequence (Kim et al, 1997). This ®nding opens the way for a better understanding of target selectivity of p53 sequence-speci®c transactivation, as it is becoming increasingly accepted that chromatin con®guration, speci®cally promoter DNA conformation, is an important determinant of promoter activation.…”

Dissociation of the recombination control and the sequence-specific transactivation function of P53

“…Sequence speci®c DNA binding by p53 also requires a certain¯exibility or secondary structures on the target DNAs and seems to be accompanied by conformational changes of p53 (Nagaich et al, 1997;Balagurumoorthy et al, 1995;Stenger et al, 1992;Kim et al, 1997). Therefore, we studied, whether these similarities between the two types of DNA interactions are re¯ected by the structural requirements on the p53 molecule.…”

Enhancement of p53 sequence-specific binding by DNA supercoiling

“…It was found that the conformational state of the target sequence in oligos is an important determinant for p53 SSDB (Kim et al, 1997;Gohler et al, 2002). The enhanced p53 SSDB observed in long DNA molecules (Espinosa and Emerson, 2001) was assigned to a hypothetical structural changes in these molecules.…”

“…The effect of DNA supercoiling in regulating the p53 biological activity and the SSDB has become a topic of interest only recently (Kim et al, 1997;Mazur et al, Palecek et al, 1997Palecek et al, , 1999Brazda et al, 2000;Brazdova et al, 2002;Jagelska et al, 2002) (for a review, see Hupp, 1999). In contrast to the prokaryotic genome, the eucaryotic genome was long believed to not be under superhelical stress due to accommodation of DNA writhing around histone octamers in nucleosomes (van Holde and Zlatanova, 1994;Pearson et al, 1996).…”