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New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins.

Golovenko D, Bräuning B, Vyas P, Haran TE, Rozenberg H, Shakked Z
Structure 26 1237-1250.e6 (2018)
Related entries: 5mct, 5mcu, 5mcv, 5mf7, 5mg7, 6fj5

Cited: 24 times
EuropePMC logo PMID: 30057026

Abstract

The tumor suppressor p53 acts as a transcription factor recognizing diverse DNA response elements (REs). Previous structural studies of p53-DNA complexes revealed non-canonical Hoogsteen geometry of A/T base pairs at conserved CATG motifs leading to changes in DNA shape and its interface with p53. To study the effects of DNA shape on binding characteristics, we designed REs with modified base pairs "locked" into either Hoogsteen or Watson-Crick form. Here we present crystal structures of these complexes and their thermodynamic and kinetic parameters, demonstrating that complexes with Hoogsteen base pairs are stabilized relative to those with all-Watson-Crick base pairs. CATG motifs are abundant in p53REs such as GADD45 and p53R2 related to cell-cycle arrest and DNA repair. The high-resolution structures of these complexes validate their propensity to adopt the unique Hoogsteen-induced structure, thus providing insights into the functional role of DNA shape and broadening the mechanisms that contribute to DNA recognition by proteins.

Reviews citing this publication (2)

  1. Facilitated Diffusion Mechanisms in DNA Base Excision Repair and Transcriptional Activation. Esadze A, Stivers JT. Chem Rev 118 11298-11323 (2018)
  2. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang H, Guo M, Wei H, Chen Y. Signal Transduct Target Ther 8 92 (2023)

Articles citing this publication (22)

  1. DNA mismatches reveal conformational penalties in protein-DNA recognition. Afek A, Shi H, Rangadurai A, Sahay H, Senitzki A, Xhani S, Fang M, Salinas R, Mielko Z, Pufall MA, Poon GMK, Haran TE, Schumacher MA, Al-Hashimi HM, Gordân R. Nature 587 291-296 (2020)
  2. Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Degtjarik O, Golovenko D, Diskin-Posner Y, Abrahmsén L, Rozenberg H, Shakked Z. Nat Commun 12 7057 (2021)
  3. New insights into protein-DNA binding specificity from hydrogen bond based comparative study. Lin M, Guo JT. Nucleic Acids Res 47 11103-11113 (2019)
  4. Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates. Farkas M, Hashimoto H, Bi Y, Davuluri RV, Resnick-Silverman L, Manfredi JJ, Debler EW, McMahon SB. Nat Commun 12 484 (2021)
  5. Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage. Xu Y, Manghrani A, Liu B, Shi H, Pham U, Liu A, Al-Hashimi HM. J Biol Chem 295 15933-15947 (2020)
  6. 20(S)-Protopanaxatriol promotes the binding of P53 and DNA to regulate the antitumor network via multiomic analysis. Wang Z, Wu W, Guan X, Guo S, Li C, Niu R, Gao J, Jiang M, Bai L, Leung EL, Hou Y, Jiang Z, Bai G. Acta Pharm Sin B 10 1020-1035 (2020)
  7. Characterizing Watson-Crick versus Hoogsteen Base Pairing in a DNA-Protein Complex Using Nuclear Magnetic Resonance and Site-Specifically 13C- and 15N-Labeled DNA. Zhou H, Sathyamoorthy B, Stelling A, Xu Y, Xue Y, Pigli YZ, Case DA, Rice PA, Al-Hashimi HM. Biochemistry 58 1963-1974 (2019)
  8. Revealing A-T and G-C Hoogsteen base pairs in stressed protein-bound duplex DNA. Shi H, Kimsey IJ, Gu S, Liu HF, Pham U, Schumacher MA, Al-Hashimi HM. Nucleic Acids Res 49 12540-12555 (2021)
  9. The complex architecture of p53 binding sites. Senitzki A, Safieh J, Sharma V, Golovenko D, Danin-Poleg Y, Inga A, Haran TE. Nucleic Acids Res 49 1364-1382 (2021)
  10. Infrared Spectroscopic Observation of a G-C+ Hoogsteen Base Pair in the DNA:TATA-Box Binding Protein Complex Under Solution Conditions. Stelling AL, Liu AY, Zeng W, Salinas R, Schumacher MA, Al-Hashimi HM. Angew Chem Int Ed Engl 58 12010-12013 (2019)
  11. Measuring thermodynamic preferences to form non-native conformations in nucleic acids using ultraviolet melting. Rangadurai A, Shi H, Xu Y, Liu B, Abou Assi H, Boom JD, Zhou H, Kimsey IJ, Al-Hashimi HM. Proc Natl Acad Sci U S A 119 e2112496119 (2022)
  12. Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines. Othman EM, Bekhit AA, Anany MA, Dandekar T, Ragab HM, Wahid A. Molecules 26 2961 (2021)
  13. Free Energy Landscape and Conformational Kinetics of Hoogsteen Base Pairing in DNA vs. RNA. Ray D, Andricioaei I. Biophys J 119 1568-1579 (2020)
  14. Force-Field-Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA. Stone SE, Ray D, Andricioaei I. J Chem Inf Model 62 6749-6761 (2022)
  15. Rapid assessment of Watson-Crick to Hoogsteen exchange in unlabeled DNA duplexes using high-power SELOPE imino 1H CEST. Liu B, Rangadurai A, Shi H, Al-Hashimi HM. Magn Reson (Gott) 2 715-731 (2021)
  16. Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency. Rigoli M, Spagnolli G, Lorengo G, Monti P, Potestio R, Biasini E, Inga A. Int J Mol Sci 23 7960 (2022)
  17. A molecular mechanism for the "digital" response of p53 to stress. Safieh J, Chazan A, Saleem H, Vyas P, Danin-Poleg Y, Ron D, Haran TE. Proc Natl Acad Sci U S A 120 e2305713120 (2023)
  18. Alchemical Free-Energy Calculations of Watson-Crick and Hoogsteen Base Pairing Interconversion in DNA. Geronimo I, De Vivo M. J Chem Theory Comput 18 6966-6973 (2022)
  19. Characterization on the oncogenic effect of the missense mutations of p53 via machine learning. Pan Q, Portelli S, Nguyen TB, Ascher DB. Brief Bioinform 25 bbad428 (2023)
  20. Deep Molecular and In Silico Protein Analysis of p53 Alteration in Myelodysplastic Neoplasia and Acute Myeloid Leukemia. Madarász K, Mótyán JA, Bedekovics J, Miltényi Z, Ujfalusi A, Méhes G, Mokánszki A. Cells 11 3475 (2022)
  21. Has-miR-300-GADD45B promotes melanoma growth via cell cycle. Chen L, Fang C, Yuan X, Liu M, Wu P, Zhong L, Chen Z. Aging (Albany NY) 15 13920-13943 (2023)
  22. Physicochemical models of protein-DNA binding with standard and modified base pairs. Chiu TP, Rao S, Rohs R. Proc Natl Acad Sci U S A 120 e2205796120 (2023)


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