C-terminal diversity within the p53 family accounts for differences in DNA binding and transcriptional activity

• Published in: Nucleic acids research Vol. 36; no. 6; pp. 1900 - 1912
• Main Authors: Sauer, Markus, Bretz, Anne Catherine, Beinoraviciute-Kellner, Rasa, Beitzinger, Michaela, Burek, Christof, Rosenwald, Andreas, Harms, Gregory S, Stiewe, Thorsten
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2008; Oxford Publishing Limited (England)
• Subjects: alternative splicing; Apoptosis; Binding Sites; Cell Cycle; cell cycle checkpoints; Cell Line; Cell Nucleus - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Deoxyribonucleic acid; Diffusion; DNA; DNA - chemistry; DNA - metabolism; DNA-binding domains; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; gene activation; genome; Humans; Molecular Biology; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; post-translational modification; Promoter Regions, Genetic; Protein Binding; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Tertiary; stress response; transcription (genetics); transcription factors; Transcription, Genetic; Tumor Protein p73; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkn044

The p53 family is known as a family of transcription factors with functions in tumor suppression and development. Whereas the central DNA-binding domain is highly conserved among the three family members p53, p63 and p73, the C-terminal domains (CTDs) are diverse and subject to alternative splicing and post-translational modification. Here we demonstrate that the CTDs strongly influence DNA binding and transcriptional activity: while p53 and the p73 isoform p73γ have basic CTDs and form weak sequence-specific protein-DNA complexes, the major p73 isoforms have neutral CTDs and bind DNA strongly. A basic CTD has been previously shown to enable sliding along the DNA backbone and to facilitate the search for binding sites in the complex genome. Our experiments, however, reveal that a basic CTD also reduces protein-DNA complex stability, intranuclear mobility, promoter occupancy in vivo, target gene activation and induction of cell cycle arrest or apoptosis. A basic CTD therefore provides both positive and negative regulatory functions presumably to enable rapid switching of protein activity in response to stress. The different DNA-binding characteristics of the p53 family members could therefore reflect their predominant role in the cellular stress response (p53) or developmental processes (p73).