Sliding into home: facilitated p53 search for targets by the basic DNA binding domain

p53 is a unique DNA binding protein with two distinct DNA binding domains, the evolutionarily conserved central domain and the C-terminal basic DNA binding domain (BD domain). The presence of two separate DNA binding domains with distinct DNA binding properties distinguishes p53 from other DNA binding proteins. Transcription factors generally bind DNA with sequence specificity but not with DNA structure specificity. DNA repair proteins generally bind DNA with structure specificity without sequence specificity. Even in the p53 gene family, the BD domain is a unique feature of vertebrate p53 proteins that is absent in p63, p73 and p53 homologues in primitive species like squid, Drosophila and Caenorhabdities. elegans. A central question is why p53 requires two DNA binding domains for its role as a tumor suppressor.

Whereas the function of the central domain has been well defined as the region that binds sequence-specific DNA (SS-DNA), the biological function of the BD domain has been a subject of debate since its identification as a separate DNA binding domain. ¹ Initially, the BD domain of p53 was postulated as a conformational regulatory mechanism to repress the SS-DNA binding activity of the central domain, based on evidence that p53 binding to its consensus DNA is activated by multiple means: truncation of the entire basic domain in p53Δ30 (360–393); replacement of the basic domain by alternative splicing; phosphorylation at 376 and 378 by protein kinase C or cyclin-activated kinase; acetylation at 373 and 382 by p300/CBP; and association with other factors like c-Abl and PAb421 antibody, which recognizes an epitope between 370 and 378 of p53 protein. The conformation model is also favored in a more recent study with purified acetyl p53 showing that acetylation of p53 enhanced binding to SS-DNA detectable by chromatin immunoprecipitation (ChIP).² However, the conformation models have been challenged by nuclear magnetic resonance analysis arguing against conformational change-induced p53 binding to DNA. The apparent BD domain repression of central domain-mediated SS-DNA binding can be explained by interference with BD domain-mediated binding to non-sequence-specific DNA (NS-DNA). Evidence for this is the ability of BD-specific antibody PAb421 to block p53 binding to NS-DNA.^{3, 4} Furthermore, the BD domain has been demonstrated to have a favorable effect on p53 binding to SS-DNA in the context of long stretches of DNA and chromatin-assembled DNA,⁵ nonlinear stem–loop DNA, and bent DNA.⁶

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