p53 Linear Diffusion along DNA Requires Its C Terminus

Abstract

In cells, sequence-specific transcription factors must search through an entire genome to find their target sites in promoters. Such sites may be identified by using one-dimensional (linear diffusion) and/or three-dimensional (association/dissociation) mechanisms. We show here that wild-type p53 possesses the ability to linearly diffuse on DNA. p53 lacking its C terminus is incapable of such sliding along DNA, while the isolated C terminus of p53 is even more effective than the full-length protein at one-dimensional linear diffusion. Importantly, neither acetylation-mimicking mutations nor phosphorylation of residues within the C terminus stimulates linear diffusion by p53. Supporting these in vitro observations, we found that C-terminally deleted p53 (p53Delta30) expressed at physiological levels is deficient in binding to and transactivating downstream promoters in vivo. Therefore, our data show that the C terminus is a positive regulator of DNA binding in vivo and in vitro, and indicate that the mechanism may involve linear diffusion.

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

“…This was confirmed by a study showing that p53 transcriptional activity is activated by PAb421 in cells (Lu and Lane, 1993). Recent studies have demonstrated that within the context of chromatin or supercoiled DNA, the C-terminal domain may actually facilitate binding of the core to its target DNA sequence by providing an additional anchorage to specific DNA sites via nonspecific DNA binding (Espinosa and Emerson, 2001;McKinney and Prives, 2002;McKinney et al, 2004).…”

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

“…Many factors may contribute to the DNA bending; other parts of the protein or base pairs flanking the p53-response elements may also be involved in triggering additional conformational change and in stabilizing the bent DNA conformation. There is evidence indicating that efficient p53 binding requires both the core domain and the C-terminal domain of the p53 protein 46,47 . In addition, base pairs other than the central 4 could also contribute to different extents.…”

Transcriptional regulation by p53: one protein, many possibilities

“…McKinney and Prives, 59 Fojta et al, 60 and Palecek et al 61 have shown that the CTD is important for binding to various non-linear DNAs. In another study, McKinney et al 62 have demonstrated the involvement of CTD in the ability of p53 to diffuse linearly on DNA. Both, McKinney et al 62 and Liu et al 63 showed as well that the CTD is required for efficient promoter activation in vivo by p53.…”

“…In another study, McKinney et al 62 have demonstrated the involvement of CTD in the ability of p53 to diffuse linearly on DNA. Both, McKinney et al 62 and Liu et al 63 showed as well that the CTD is required for efficient promoter activation in vivo by p53. Moreover, Harms and Chen 64 have recently reported that the CTD inhibits p53-dependent induction of IGFBP3 gene.…”