Characterization of the p53 Cistrome – DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions

English version České info

p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context -⁠ and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.

Vyšlo v časopise: Characterization of the p53 Cistrome – DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003726
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003726

Souhrn

Zdroje

1. VousdenKH, LaneDP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8 : 275–283.

2. VogelsteinB, LaneD, LevineAJ (2000) Surfing the p53 network. Nature 408 : 307–310.

3. StieweT (2007) The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 7 : 165–168.

4. VousdenKH, PrivesC (2009) Blinded by the Light: The Growing Complexity of p53. Cell 137 : 413–431.

5. BeckermanR, PrivesC (2010) Transcriptional regulation by p53. Cold Spring Harbor perspectives in biology 2: a000935.

6. RinnJL, HuarteM (2011) To repress or not to repress: this is the guardian's question. Trends in cell biology 21 : 344–353.

7. LohrK, MoritzC, ContenteA, DobbelsteinM (2003) p21/CDKN1A mediates negative regulation of transcription by p53. The Journal of biological chemistry 278 : 32507–32516.

8. CarvajalLA, HamardPJ, TonnessenC, ManfrediJJ (2012) E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes & development 26 : 1533–1545.

9. AksoyO, ChicasA, ZengT, ZhaoZ, McCurrachM, et al. (2012) The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence. Genes & development 26 : 1546–1557.

10. HeL, HeX, LimLP, de StanchinaE, XuanZ, et al. (2007) A microRNA component of the p53 tumour suppressor network. Nature 447 : 1130–1134.

11. SuzukiHI, YamagataK, SugimotoK, IwamotoT, KatoS, et al. (2009) Modulation of microRNA processing by p53. Nature 460 : 529–533.

12. HuarteM, GuttmanM, FeldserD, GarberM, KoziolMJ, et al. (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142 : 409–419.

13. RileyT, SontagE, ChenP, LevineA (2008) Transcriptional control of human p53-regulated genes. Nature reviews Molecular cell biology 9 : 402–412.

14. BalagurumoorthyP, LindsaySM, HarringtonRE (2002) Atomic force microscopy reveals kinks in the p53 response element DNA. Biophysical chemistry 101–102 : 611–623.

15. BenoI, RosenthalK, LevitineM, ShaulovL, HaranTE (2011) Sequence-dependent cooperative binding of p53 to DNA targets and its relationship to the structural properties of the DNA targets. Nucleic acids research 39 : 1919–1932.

16. WeinbergRL, VeprintsevDB, BycroftM, FershtAR (2005) Comparative binding of p53 to its promoter and DNA recognition elements. Journal of molecular biology 348 : 589–596.

17. JordanJJ, MenendezD, IngaA, NoureddineM, BellDA, et al. (2008) Noncanonical DNA motifs as transactivation targets by wild type and mutant p53. PLoS genetics 4: e1000104.

18. MenendezD, IngaA, ResnickMA (2009) The expanding universe of p53 targets. Nature reviews Cancer 9 : 724–737.

19. ChoY, GorinaS, JeffreyPD, PavletichNP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265 : 346–355.

20. KitaynerM, RozenbergH, KesslerN, RabinovichD, ShaulovL, et al. (2006) Structural basis of DNA recognition by p53 tetramers. Molecular cell 22 : 741–753.

21. WeinbergRL, VeprintsevDB, FershtAR (2004) Cooperative binding of tetrameric p53 to DNA. Journal of molecular biology 341 : 1145–1159.

22. DehnerA, KleinC, HansenS, MullerL, BuchnerJ, et al. (2005) Cooperative binding of p53 to DNA: regulation by protein-protein interactions through a double salt bridge. Angewandte Chemie 44 : 5247–5251.

23. KleinC, PlankerE, DiercksT, KesslerH, KunkeleKP, et al. (2001) NMR spectroscopy reveals the solution dimerization interface of p53 core domains bound to their consensus DNA. The Journal of biological chemistry 276 : 49020–49027.

24. SchlerethK, Beinoraviciute-KellnerR, ZeitlingerMK, BretzAC, SauerM, et al. (2010) DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Molecular cell 38 : 356–368.

25. TimofeevO, SchlerethK, WanzelM, BraunA, NieswandtB, et al. (2013) p53 DNA Binding Cooperativity is Essential for Apoptosis and Tumor Suppression In Vivo. Cell Reports 3 : 1512–25 http://dx.doi.org/10.1016/j.celrep.2013.1004.1008.

26. VassilevLT, VuBT, GravesB, CarvajalD, PodlaskiF, et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303 : 844–848.

27. HohJ, JinS, ParradoT, EdingtonJ, LevineAJ, et al. (2002) The p53MH algorithm and its application in detecting p53-responsive genes. Proceedings of the National Academy of Sciences of the United States of America 99 : 8467–8472.

28. PerezCA, OttJ, MaysDJ, PietenpolJA (2007) p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm. Oncogene 26 : 7363–7370.

29. RouaultJP, FaletteN, GuehenneuxF, GuillotC, RimokhR, et al. (1996) Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nature genetics 14 : 482–486.

30. el-DeiryWS, TokinoT, VelculescuVE, LevyDB, ParsonsR, et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75 : 817–825.

31. SmeenkL, van HeeringenSJ, KoeppelM, GilbertB, Janssen-MegensE, et al. (2011) Role of p53 serine 46 in p53 target gene regulation. PloS one 6: e17574.

32. NikulenkovF, SpinnlerC, LiH, TonelliC, ShiY, et al. (2012) Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell death and differentiation 19 : 1992–2002.

33. WeiCL, WuQ, VegaVB, ChiuKP, NgP, et al. (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124 : 207–219.

34. ContenteA, DittmerA, KochMC, RothJ, DobbelsteinM (2002) A polymorphic microsatellite that mediates induction of PIG3 by p53. Nature genetics 30 : 315–320.

35. MillerLD, SmedsJ, GeorgeJ, VegaVB, VergaraL, et al. (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102 : 13550–13555.

36. TroesterMA, HerschkowitzJI, OhDS, HeX, HoadleyKA, et al. (2006) Gene expression patterns associated with p53 status in breast cancer. BMC cancer 6 : 276.

37. van de VijverMJ, HeYD, van't VeerLJ, DaiH, HartAAM, et al. (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347 : 1999–2009.

38. MizunoH, SpikeBT, WahlGM, LevineAJ (2010) Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures. Proc Natl Acad Sci USA

39. LiM, HeY, DuboisW, WuX, ShiJ, et al. (2012) Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Molecular cell 46 : 30–42.

40. OngCT, CorcesVG (2012) Enhancers: emerging roles in cell fate specification. EMBO reports 13 : 423–430.

41. BulgerM, GroudineM (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144 : 327–339.

42. KelA, VossN, JaureguiR, Kel-MargoulisO, WingenderE (2006) Beyond microarrays: find key transcription factors controlling signal transduction pathways. BMC bioinformatics 7(Suppl 2): S13.

43. HermekingH (2012) MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature reviews Cancer 12 : 613–626.

44. SchlerethK, CharlesJP, BretzAC, StieweT (2010) Life or death: p53-induced apoptosis requires DNA binding cooperativity. Cell cycle 9 : 4068–4076.

45. BalagurumoorthyP, SakamotoH, LewisMS, ZambranoN, CloreGM, et al. (1995) Four p53 DNA-binding domain peptides bind natural p53-response elements and bend the DNA. Proceedings of the National Academy of Sciences of the United States of America 92 : 8591–8595.

46. HorvathMM, WangX, ResnickMA, BellDA (2007) Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS genetics 3: e127.

47. MenendezD, KrysiakO, IngaA, KrysiakB, ResnickMA, et al. (2006) A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network. Proceedings of the National Academy of Sciences of the United States of America 103 : 1406–1411.

48. JeggaAG, IngaA, MenendezD, AronowBJ, ResnickMA (2008) Functional evolution of the p53 regulatory network through its target response elements. Proceedings of the National Academy of Sciences of the United States of America 105 : 944–949.

49. MenendezD, IngaA, SnipeJ, KrysiakO, SchonfelderG, et al. (2007) A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Molecular and cellular biology 27 : 2590–2600.

50. ShakedH, ShiffI, Kott-GutkowskiM, SiegfriedZ, HauptY, et al. (2008) Chromatin immunoprecipitation-on-chip reveals stress-dependent p53 occupancy in primary normal cells but not in established cell lines. Cancer research 68 : 9671–9677.

51. VrbaL, JunkDJ, NovakP, FutscherBW (2008) p53 induces distinct epigenetic states at its direct target promoters. BMC genomics 9 : 486.

52. EspinosaJM, VerdunRE, EmersonBM (2003) p53 functions through stress -⁠ and promoter-specific recruitment of transcription initiation components before and after DNA damage. Molecular cell 12 : 1015–1027.

53. JacksonJG, PantV, LiQ, ChangLL, Quintas-CardamaA, et al. (2012) p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21 : 793–806.

54. MathieuMC, KoscielnyS, Le BihanML, SpielmannM, ArriagadaR (1995) p53 protein overexpression and chemosensitivity in breast cancer. Institut Gustave-Roussy Breast Cancer Group. Lancet 345 : 1182.

55. BertheauP, TurpinE, RickmanDS, EspieM, de ReyniesA, et al. (2007) Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen. PLoS medicine 4: e90.

56. BertheauP, PlassaF, EspieM, TurpinE, de RoquancourtA, et al. (2002) Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy. Lancet 360 : 852–854.

57. HoJS, MaW, MaoDY, BenchimolS (2005) p53-Dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Molecular and cellular biology 25 : 7423–7431.

58. GrinkevichVV, NikulenkovF, ShiY, EngeM, BaoW, et al. (2009) Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. Cancer Cell 15 : 441–453.

59. BradyCA, JiangD, MelloSS, JohnsonTM, JarvisLA, et al. (2011) Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145 : 571–583.

60. ChangTC, WentzelEA, KentOA, RamachandranK, MullendoreM, et al. (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular cell 26 : 745–752.

61. Raver-ShapiraN, MarcianoE, MeiriE, SpectorY, RosenfeldN, et al. (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Molecular cell 26 : 731–743.

62. GorinaS, PavletichNP (1996) Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274 : 1001–1005.

63. Samuels-LevY, O'ConnorDJ, BergamaschiD, TrigianteG, HsiehJK, et al. (2001) ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 8 : 781–794.

64. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome biology 10: R25.

65. MachanickP, BaileyTL (2011) MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics 27 : 1696–1697.

66. GuptaS, StamatoyannopoulosJA, BaileyTL, NobleWS (2007) Quantifying similarity between motifs. Genome biology 8: R24.

67. GrantCE, BaileyTL, NobleWS (2011) FIMO: scanning for occurrences of a given motif. Bioinformatics 27 : 1017–1018.

68. BaileyTL, GribskovM (1998) Methods and statistics for combining motif match scores. Journal of computational biology : a journal of computational molecular cell biology 5 : 211–221.

69. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America 102 : 15545–15550.

70. ChangJT, NevinsJR (2006) GATHER: a systems approach to interpreting genomic signatures. Bioinformatics 22 : 2926–2933.

71. DunhamI, KundajeA, AldredSF, CollinsPJ, DavisCA, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489 : 57–74.