The P53 C Terminus Controls Site-specific DNA Binding and Promotes Structural Changes Within the Central DNA Binding Domain

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Mar 22

PMID 25794615

Citations 75

Authors

Oleg Laptenko

Idit Shiff

Will Freed-Pastor

Andrew Zupnick

Melissa Mattia

Ella Freulich

Inbal Shamir

Noam Kadouri

Tamar Kahan

James Manfredi

Itamar Simon

Carol Prives

Affiliations

Soon will be listed here.

Abstract

DNA binding by numerous transcription factors including the p53 tumor suppressor protein constitutes a vital early step in transcriptional activation. While the role of the central core DNA binding domain (DBD) of p53 in site-specific DNA binding has been established, the contribution of the sequence-independent C-terminal domain (CTD) is still not well understood. We investigated the DNA-binding properties of a series of p53 CTD variants using a combination of in vitro biochemical analyses and in vivo binding experiments. Our results provide several unanticipated and interconnected findings. First, the CTD enables DNA binding in a sequence-dependent manner that is drastically altered by either its modification or deletion. Second, dependence on the CTD correlates with the extent to which the p53 binding site deviates from the canonical consensus sequence. Third, the CTD enables stable formation of p53-DNA complexes to divergent binding sites via DNA-induced conformational changes within the DBD itself.

Citing Articles

Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells.

Wu Y, Zhong A, Sidharta M, Kim T, Ramirez B, Persily B Nat Commun. 2024; 15(1):10824.

PMID: 39737975 PMC: 11685797. DOI: 10.1038/s41467-024-55104-1.

Identification of methylation-sensitive human transcription factors using meSMiLE-seq.

Gralak A, Faltejskova K, Yang A, Steiner C, Russeil J, Grenningloh N bioRxiv. 2024; .

PMID: 39605503 PMC: 11601298. DOI: 10.1101/2024.11.11.619598.

How does p53 work? Regulation by the intrinsically disordered domains.

Dyson H, Wright P Trends Biochem Sci. 2024; 50(1):9-17.

PMID: 39578215 PMC: 11698644. DOI: 10.1016/j.tibs.2024.10.009.

The conformation of FOXM1 homodimers in vivo is crucial for regulating transcriptional activities.

Hsu C, Yao X, Chen S, Tsuo T, Wang I Nucleic Acids Res. 2024; 52(22):13625-13643.

PMID: 39535028 PMC: 11662942. DOI: 10.1093/nar/gkae988.

TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review).

Tornesello M Int J Mol Med. 2024; 55(1).

PMID: 39450536 PMC: 11554381. DOI: 10.3892/ijmm.2024.5448.

References

Schlereth K, Beinoraviciute-Kellner R, Zeitlinger M, Bretz A, Sauer M, Charles J . DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell. 2010; 38(3):356-68. DOI: 10.1016/j.molcel.2010.02.037. View

Laptenko O, Prives C . Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ. 2006; 13(6):951-61. DOI: 10.1038/sj.cdd.4401916. View

Jayaraman J, Prives C . Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus. Cell. 1995; 81(7):1021-9. DOI: 10.1016/s0092-8674(05)80007-8. View

Nakamura S, Roth J, Mukhopadhyay T . Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Mol Cell Biol. 2000; 20(24):9391-8. PMC: 102195. DOI: 10.1128/MCB.20.24.9391-9398.2000. View

Laptenko O, Beckerman R, Freulich E, Prives C . p53 binding to nucleosomes within the p21 promoter in vivo leads to nucleosome loss and transcriptional activation. Proc Natl Acad Sci U S A. 2011; 108(26):10385-90. PMC: 3127872. DOI: 10.1073/pnas.1105680108. View

Gopinath S . Methods developed for SELEX. Anal Bioanal Chem. 2006; 387(1):171-82. DOI: 10.1007/s00216-006-0826-2. View

Cho Y, Gorina S, Jeffrey P, Pavletich N . Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994; 265(5170):346-55. DOI: 10.1126/science.8023157. View

Laptenko O, Lee J, Lomakin I, Borukhov S . Transcript cleavage factors GreA and GreB act as transient catalytic components of RNA polymerase. EMBO J. 2003; 22(23):6322-34. PMC: 291851. DOI: 10.1093/emboj/cdg610. View

Ito A, Lai C, Zhao X, Saito S, Hamilton M, Appella E . p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 2001; 20(6):1331-40. PMC: 145533. DOI: 10.1093/emboj/20.6.1331. View

10.

Huggins P, Zhong S, Shiff I, Beckerman R, Laptenko O, Prives C . DECOD: fast and accurate discriminative DNA motif finding. Bioinformatics. 2011; 27(17):2361-7. PMC: 3157928. DOI: 10.1093/bioinformatics/btr412. View

11.

Hoh J, Jin S, Parrado T, Edington J, Levine A, Ott J . The p53MH algorithm and its application in detecting p53-responsive genes. Proc Natl Acad Sci U S A. 2002; 99(13):8467-72. PMC: 124275. DOI: 10.1073/pnas.132268899. View

12.

Anderson M, Woelker B, Reed M, Wang P, Tegtmeyer P . Reciprocal interference between the sequence-specific core and nonspecific C-terminal DNA binding domains of p53: implications for regulation. Mol Cell Biol. 1997; 17(11):6255-64. PMC: 232476. DOI: 10.1128/MCB.17.11.6255. View

13.

Olivier M, Hollstein M, Hainaut P . TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010; 2(1):a001008. PMC: 2827900. DOI: 10.1101/cshperspect.a001008. View

14.

Trauger J, Dervan P . Footprinting methods for analysis of pyrrole-imidazole polyamide/DNA complexes. Methods Enzymol. 2001; 340:450-66. DOI: 10.1016/s0076-6879(01)40436-8. View

15.

Tidow H, Melero R, Mylonas E, Freund S, Grossmann J, Carazo J . Quaternary structures of tumor suppressor p53 and a specific p53 DNA complex. Proc Natl Acad Sci U S A. 2007; 104(30):12324-9. PMC: 1941468. DOI: 10.1073/pnas.0705069104. View

16.

Gu J, Nie L, Wiederschain D, Yuan Z . Identification of p53 sequence elements that are required for MDM2-mediated nuclear export. Mol Cell Biol. 2001; 21(24):8533-46. PMC: 100016. DOI: 10.1128/MCB.21.24.8533-8546.2001. View

17.

Piluso L, Wei G, Li A, Liu X . Purification of acetyl-p53 using p300 co-infection and the baculovirus expression system. Protein Expr Purif. 2005; 40(2):370-8. DOI: 10.1016/j.pep.2004.12.015. View

18.

Feng L, Lin T, Uranishi H, Gu W, Xu Y . Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol. 2005; 25(13):5389-95. PMC: 1157004. DOI: 10.1128/MCB.25.13.5389-5395.2005. View

19.

Funk W, Pak D, Karas R, Wright W, Shay J . A transcriptionally active DNA-binding site for human p53 protein complexes. Mol Cell Biol. 1992; 12(6):2866-71. PMC: 364481. DOI: 10.1128/mcb.12.6.2866-2871.1992. View

20.

Frith M, Saunders N, Kobe B, Bailey T . Discovering sequence motifs with arbitrary insertions and deletions. PLoS Comput Biol. 2008; 4(4):e1000071. PMC: 2323616. DOI: 10.1371/journal.pcbi.1000071. View