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Cited by 30

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iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen, Shuo, Wu, Jiale, Zhong, Shan, Li, Yuntong, Zhang, Ping, Ma, Jingyi, Ren, Jingshan, Tan, Yun, Wang, Yunhao, Au, Kin Fai, Siebold, Christian, Bond, Gareth L., Chen, Zhu, Lu, Min, Jones, E. Yvonne, Lu, Xin·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1909393116
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Abstract

The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53–iASPP crystal structure reveals that iASPP displaces the p53 L1 loop—which mediates sequence-specific interactions with the signature-corresponding base—without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF–DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain—except the oncogenic E6 from human papillomaviruses (HPVs)—structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

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Research works printed but not linked: 64

  1. C. O. Pabo, R. T. Sauer, Transcription factors: Structural families and principles of DNA recognition. Annu. Rev. Biochem. 61, 1053–1095 (1992). · DOI · Paper page
  2. E. Morgunova, J. Taipale, Structural perspective of cooperative transcription factor binding. Curr. Opin. Struct. Biol. 47, 1–8 (2017). · DOI · Paper page
  3. K. Oda ., p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000). · DOI · Paper page
  4. Y. Tang, J. Luo, W. Zhang, W. Gu, Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 24, 827–839 (2006). · DOI · Paper page
  5. L. Di Croce ., Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002). · DOI · Paper page
  6. V. V. Ogryzko, R. L. Schiltz, V. Russanova, B. H. Howard, Y. Nakatani, The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996). · DOI · Paper page
  7. Y. Pan, C. J. Tsai, B. Ma, R. Nussinov, Mechanisms of transcription factor selectivity. Trends Genet. 26, 75–83 (2010). · DOI
  8. S. Inukai, K. H. Kock, M. L. Bulyk, Transcription factor-DNA binding: Beyond binding site motifs. Curr. Opin. Genet. Dev. 43, 110–119 (2017). · DOI · Paper page
  9. C. Kandoth ., Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013). · DOI · Paper page
  10. A. Zehir ., Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017). · DOI · Paper page
  11. K. H. Vousden, C. Prives, Blinded by the light: The growing complexity of p53. Cell 137, 413–431 (2009). · DOI · Paper page
  12. M. Fischer, Census and evaluation of p53 target genes. Oncogene 36, 3943–3956 (2017). · DOI · Paper page
  13. E. R. Kastenhuber, S. W. Lowe, Putting p53 in context. Cell 170, 1062–1078 (2017). · DOI · Paper page
  14. W. S. el-Deiry, S. E. Kern, J. A. Pietenpol, K. W. Kinzler, B. Vogelstein, Definition of a consensus binding site for p53. Nat. Genet. 1, 45–49 (1992). · DOI · Paper page
  15. M. Kitayner ., Structural basis of DNA recognition by p53 tetramers. Mol. Cell 22, 741–753 (2006). · DOI · Paper page
  16. A. C. Joerger, A. R. Fersht, Structural biology of the tumor suppressor p53. Annu. Rev. Biochem. 77, 557–582 (2008). · DOI · Paper page
  17. Y. Chen, R. Dey, L. Chen, Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer. Structure 18, 246–256 (2010). · DOI · Paper page
  18. T. J. Petty ., An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity. EMBO J. 30, 2167–2176 (2011). · DOI · Paper page
  19. Y. Chen ., Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion. Nucleic Acids Res. 41, 8368–8376 (2013). · DOI · Paper page
  20. S. Emamzadah, L. Tropia, T. D. Halazonetis, Crystal structure of a multidomain human p53 tetramer bound to the natural CDKN1A (p21) p53-response element. Mol. Cancer Res. 9, 1493–1499 (2011). · DOI
  21. M. A. Resnick, A. Inga, Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc. Natl. Acad. Sci. U.S.A. 100, 9934–9939 (2003). · DOI · Paper page
  22. A. Zupnick, C. Prives, Mutational analysis of the p53 core domain L1 loop. J. Biol. Chem. 281, 20464–20473 (2006). · DOI
  23. E. Arbely ., Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration. Proc. Natl. Acad. Sci. U.S.A. 108, 8251–8256 (2011). · DOI
  24. Y. Pan, C. J. Tsai, B. Ma, R. Nussinov, How do transcription factors select specific binding sites in the genome? Nat. Struct. Mol. Biol. 16, 1118–1120 (2009). · DOI
  25. D. Bergamaschi ., iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 33, 162–167 (2003). · DOI · Paper page
  26. K. Iwabuchi, P. L. Bartel, B. Li, R. Marraccino, S. Fields, Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl. Acad. Sci. U.S.A. 91, 6098–6102 (1994). · DOI · Paper page
  27. S. Gorina, N. P. Pavletich, Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274, 1001–1005 (1996). · DOI · Paper page
  28. R. A. Robinson, X. Lu, E. Y. Jones, C. Siebold, Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73. Structure 16, 259–268 (2008). · DOI
  29. D. Bergamaschi ., iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat. Genet. 38, 1133–1141 (2006). · DOI · Paper page
  30. J. Ahn, I. J. Byeon, C. H. Byeon, A. M. Gronenborn, Insight into the structural basis of pro- and antiapoptotic p53 modulation by ASPP proteins. J. Biol. Chem. 284, 13812–13822 (2009). · DOI
  31. R. J. Ihry ., p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat. Med. 24, 939–946 (2018). · DOI · Paper page
  32. D. Kenzelmann Broz ., Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev. 27, 1016–1031 (2013). · DOI · Paper page
  33. J. Zeron-Medina ., A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell 155, 410–422 (2013). · DOI · Paper page
  34. A. Sullivan, X. Lu, ASPP: A new family of oncogenes and tumour suppressor genes. Br. J. Cancer 96, 196–200 (2007). · DOI · Paper page
  35. F. A. Scholl, P. McLoughlin, E. Ehler, C. de Giovanni, B. W. Schäfer, DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis. J. Cell Biol. 151, 495–506 (2000). · DOI
  36. J. Sun, G. Yan, A. Ren, B. You, J. K. Liao, FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1. Circ. Res. 99, 468–476 (2006). · DOI
  37. X. Zhang ., Rap2b, a novel p53 target, regulates p53-mediated pro-survival function. Cell Cycle 12, 1279–1291 (2013). · DOI
  38. Y. Zhao, M. Tan, X. Liu, X. Xiong, Y. Sun, Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2-MRN-ATM axes. Cell Death Dis. 9, 145 (2018). · DOI
  39. C. Bersani, L. D. Xu, A. Vilborg, W. O. Lui, K. G. Wiman, Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3σ. Oncogene 33, 4407–4417 (2014). · DOI
  40. D. C. Guo ., Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am. J. Hum. Genet. 84, 617–627 (2009). · DOI · Paper page
  41. R. Kageyama, T. Ohtsuka, T. Kobayashi, The Hes gene family: Repressors and oscillators that orchestrate embryogenesis. Development 134, 1243–1251 (2007). · DOI · Paper page
  42. E. Bafaro, Y. Liu, Y. Xu, R. E. Dempski, The emerging role of zinc transporters in cellular homeostasis and cancer. Signal Transduct. Target. Ther. 2, 17029 (2017). · DOI · Paper page
  43. K. Bensaad ., TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006). · DOI · Paper page
  44. A. C. Joerger, H. C. Ang, A. R. Fersht, Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc. Natl. Acad. Sci. U.S.A. 103, 15056–15061 (2006). · DOI · Paper page
  45. H. Tidow, D. B. Veprintsev, S. M. Freund, A. R. Fersht, Effects of oncogenic mutations and DNA response elements on the binding of p53 to p53-binding protein 2 (53BP2). J. Biol. Chem. 281, 32526–32533 (2006). · DOI
  46. W. S. Joo ., Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev. 16, 583–593 (2002). · DOI · Paper page
  47. A. V. Follis ., The DNA-binding domain mediates both nuclear and cytosolic functions of p53. Nat. Struct. Mol. Biol. 21, 535–543 (2014). · DOI · Paper page
  48. W. Lilyestrom, M. G. Klein, R. Zhang, A. Joachimiak, X. S. Chen, Crystal structure of SV40 large T-antigen bound to p53: Interplay between a viral oncoprotein and a cellular tumor suppressor. Genes Dev. 20, 2373–2382 (2006). · DOI · Paper page
  49. D. Martinez-Zapien ., Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529, 541–545 (2016). · DOI · Paper page
  50. J. G. Omichinski ., NMR structure of a specific DNA complex of Zn-containing DNA binding domain of GATA-1. Science 261, 438–446 (1993). · DOI · Paper page
  51. S. K. Singh ., Structural visualization of the p53/RNA polymerase II assembly. Genes Dev. 30, 2527–2537 (2016). · doi:10.1101/gad.285692.116
  52. M. Notari ., iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death. Proc. Natl. Acad. Sci. U.S.A. 112, E973–E981 (2015). · DOI
  53. T. C. Falik-Zaccai ., Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome. EMBO Mol. Med. 9, 319–336 (2017). · DOI
  54. Z. Wu ., Inhibitory member of the apoptosis-stimulating protein of p53 is overexpressed in bladder cancer and correlated to its progression. Medicine (Baltimore) 96, e6640 (2017). · DOI
  55. Y. Xue ., iASPP facilitates tumor growth by promoting mTOR-dependent autophagy in human non-small-cell lung cancer. Cell Death Dis. 8, e3150 (2017). · doi:10.1038/cddis.2017.515
  56. K. K. Chan ., Impact of iASPP on chemoresistance through PLK1 and autophagy in ovarian clear cell carcinoma. Int. J. Cancer 143, 1456–1469 (2018). · DOI
  57. L. Yin ., The family of apoptosis-stimulating proteins of p53 is dysregulated in colorectal cancer patients. Oncol. Lett. 15, 6409–6417 (2018).
  58. Z. Cheng ., Enhanced expressions of FHL2 and iASPP predict poor prognosis in acute myeloid leukemia. Cancer Gene Ther. 26, 17–25 (2019). · doi:10.1038/s41417-018-0027-0
  59. W. Lu ., FHL2 interacts with iASPP and impacts the biological functions of leukemia cells. Oncotarget 8, 40885–40895 (2017). · DOI
  60. S. Emamzadah, L. Tropia, I. Vincenti, B. Falquet, T. D. Halazonetis, Reversal of the DNA-binding-induced loop L1 conformational switch in an engineered human p53 protein. J. Mol. Biol. 426, 936–944 (2014). · DOI
  61. C. D. Wassman ., Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nat. Commun. 4, 1407 (2013). · DOI · Paper page
  62. A. Friedler ., A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants. Proc. Natl. Acad. Sci. U.S.A. 99, 937–942 (2002). · DOI · Paper page
  63. N. Issaeva ., Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc. Natl. Acad. Sci. U.S.A. 100, 13303–13307 (2003). · DOI · Paper page
  64. S. Chen ., Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Dev. Cell 21, 848–861 (2011). · DOI

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Metadata

Authors
Chen, S., Wu, J., Zhong, S., Li, Y., Zhang, P., Ma, J., Ren, J., Tan, Y., Wang, Y., Au, K. F., Siebold, C., Bond, G. L., Chen, Z., Lu, M., Jones, E. Y., & Lu, X.
Affiliations
  • Ludwig Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
  • State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
  • Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
  • Department of Internal Medicine, University of Iowa, Iowa City, IA 52242;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-08-08
Volume
116
Issue
35
Pages
17470-17479
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1909393116
Cited by
30
References
9
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Ludwig Institute for Cancer Research (Oxford)
  • DH | National Institute for Health Research (Oxford Biomedical Research Centre)
  • National Key R&D Program of China (2017YFA0506200)
  • National Natural Science Foundation of China (NSFC81622002)
  • Cancer Research UK (C375/A17721)
  • Wellcome (203141/Z/16/Z)

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CoChat. (2026). Citation check: iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition. https://app.cochat.ai/papers/10.1073/pnas.1909393116
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Chen, S., Wu, J., Zhong, S., Li, Y., Zhang, P., Ma, J., Ren, J., Tan, Y., Wang, Y., Au, K. F., Siebold, C., Bond, G. L., Chen, Z., Lu, M., Jones, E. Y., & Lu, X. (2019). iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1909393116

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