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快乐十分复式投注表图:Interaction between p53 N terminus and core domain regulates specific and nonspecific DNA binding
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The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. This report investigates the role of the p53 N-terminal transactivation domain in regulating DNA binding affinity and specificity. The results suggest the N-terminal acidic transactivation region of p53 dynamically interacts with the DNA binding domain near residues that contact DNA, thus inhibiting DNA binding and increasing sequence specificity by nucleic acid mimicry or electrostatic shielding. Furthermore, p53 N-terminal–interacting proteins and posttranslational modifications may regulate DNA binding affinity and specificity partly by modulating the N terminus–DNA binding domain interaction.
The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. Dynamic control of p53 degradation and DNA binding in response to stress signals are critical for tumor suppression. The p53 N terminus (NT) contains two transactivation domains (TAD1 and TAD2), a proline-rich region (PRR), and multiple phosphorylation sites. Previous work revealed the p53 NT reduced DNA binding in vitro. Here, we show that TAD2 and the PRR inhibit DNA binding by directly interacting with the sequence-specific DNA binding domain (DBD). NMR spectroscopy revealed that TAD2 and the PRR interact with the DBD at or near the DNA binding surface, possibly acting as a nucleic acid mimetic to competitively block DNA binding. In vitro and in vivo DNA binding analyses showed that the NT reduced p53 DNA binding affinity but improved the ability of p53 to distinguish between specific and nonspecific sequences. MDMX inhibits p53 binding to specific target promoters but stimulates binding to nonspecific chromatin sites. The results suggest that the p53 NT regulates the affinity and specificity of DNA binding by the DBD. The p53 NT-interacting proteins and posttranslational modifications may regulate DNA binding, partly by modulating the NT–DBD interaction.
?1F.H. and W.B. contributed equally to this work.
?2Present address: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China, 430073.
?3Present address: Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China, 300060.
?4Present address: Department of Microbiology, PDM University, Haryana, India, 124507.
- ?5To whom correspondence may be addressed. Email: or .
Author contributions: F.H., W.B, T.S., X.W., G.W.D., and J.C. designed research; F.H., W.B., T.S., and X.W. performed research; M.D. and L.C. contributed new reagents/analytic tools; F.H., W.B., T.S., X.W., G.W.D., and J.C. analyzed data; and F.H., W.B., G.W.D., and J.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1903077116/-/DCSupplemental.
Published under the PNAS license.