Купить новостройку с отделкой. Где купить однокомнатную квартиру в новостройке? Купить новостройку недорого. Оценка стоимости недвижимости. Какая рыночная оценка недвижимости? Принципы оценки недвижимости. Теплый пол своими руками. Как сделать теплый пол в доме. Монтаж водяного теплого пола. Не включается ноутбук. Скажите почему не включается ноутбук. Ноутбук включается и сразу выключается. Быстрый кредит наличными. Где быстро взять кредит без справок. Оформить быстрый кредит. Топ wow сервера. Где скачать последний клиент wow? Самый лучший сервера world of warcraft. Ленточная пилорама цена. Ленточная пилорама своими руками чертежи. Скачать чертежи ленточной пилорамы. Аренда квартир без посредников. Длительная аренда квартир без посредников и прочих. Аренда однокомнатной квартиры.

Methylation-Acetylation Interplay Activates p53 in Response to DNA Damage

Gleb S. Ivanov, Tatyana Ivanova, Julia Kurash, Alexey Ivanov, Sergey Chuikov, Farid Gizatullin, Enrique M. Herrera-Medina, Frank Rauscher III, Danny Reinberg, and Nickolai A. Barlev


MOLECULAR AND CELLULAR BIOLOGY, Oct. 2007, p. 6756–6769, Vol. 27, No. 19


Читать статью


p53, an important tumor suppressor protein, exerts its function mostly as a sequence-specific transcription factor and is subjected to multiple posttranslational modifications in response to genotoxic stress. Recently, we discovered that lysine methylation of p53 at K372 by Set7/9 (also known as SET7 and Set9) is important for transcriptional activation and stabilization of p53. In this report we provide a molecular mechanism for the effect of p53 methylation on transcription. We demonstrate that Set7/9 activity toward p53, but not the nucleosomal histones, is modulated by DNA damage. Significantly, we show that lysine methylation of p53 is important for its subsequent acetylation, resulting in stabilization of the p53 protein. These p53 modification events can be observed on the promoter of p21 gene, a known transcriptional target of p53. Finally, we show that methylation-acetylation interplay in p53 augments acetylation of histone H4 in the promoter of p21 gene, resulting in its subsequent transcriptional activation and, hence, cell cycle arrest. Collectively, these results suggest that the cross talk between lysine methylation and acetylation is critical for p53 activation in response to DNA damage and that Set7/9 may play an important role in tumor suppression.


1. Appella, E., and C. W. Anderson. 2001. Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 268:2764–2772.

2. Barlev, N. A., L. Liu, N. H. Chehab, K. Mansfield, K. G. Harris, T. D. Halazonetis, and S. L. Berger. 2001. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol. Cell 8:1243–1254.

3. Basile, V., R. Mantovani, and C. Imbriano. 2006. DNA damage promotes histone deacetylase 4 nuclear localization and repression of G2/M promoters, via p53 C-terminal lysines. J. Biol. Chem. 281:2347–2357.

4. Benton, M. G., S. Somasundaram, J. D. Glasner, and S. P. Palecek. 2006. Analyzing the dose-dependence of the Saccharomyces cerevisiae global transcriptional response to methyl methanesulfonate and ionizing radiation. BMC Genomics 7:305.

5. Bode, A. M., and Z. Dong. 2004. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer 4:793–805.

6. Brooks, C. L., and W. Gu. 2006. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21:307–315.

7. Brooks, C. L., and W. Gu. 2003. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell Biol. 15: 164–171.

8. Brown, M. A., R. J. Sims III, P. D. Gottlieb, and P. W. Tucker. 2006. Identification and characterization of Smyd2: a split SET/MYND domaincontaining histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol. Cancer 5:26.

9. Bunz, F., A. Dutriaux, C. Lengauer, T. Waldman, S. Zhou, J. P. Brown, J. M. Sedivy, K. W. Kinzler, and B. Vogelstein. 1998. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501.

10. Ceribelli, M., M. Alcalay, M. A. Vigano, and R. Mantovani. 2006. Repression of new p53 targets revealed by ChIP on chip experiments. Cell Cycle 5:1102–1110.

11. Ceskova, P., H. Chichger, M. Wallace, B. Vojtesek, and T. R. Hupp. 2006. On the mechanism of sequence-specific DNA-dependent acetylation of p53: the acetylation motif is exposed upon DNA binding. J. Mol. Biol. 357:442–456.

12. Chuikov, S., Y. Kurash, J. R. Wilson, B. Xiao, N. Justin, G. Ivanov, K. McKinney, P. Tempst, C. Prives, S. Gamblin, N. Barlev, and D. Reinberg. 2004. Regulation of p53 activity through lysine methylation. Nature 432:353–360.

13. Dignam, J. D., R. M. Lebovitz, and R. G. Roeder. 1983. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11:1475–1489.

14. Dornan, D., H. Shimizu, N. D. Perkins, and T. R. Hupp. 2003. DNAdependent acetylation of p53 by the transcription coactivator p300. J. Biol.
Chem. 278:13431–13441.

15. el Deiry, W., T. Tokino, V. E. Velculescu, D. B. Levy, R. Parsons, J. M. Trent, D. Lin, W. E. Mercer, K. W. Kinzler, and B. Vogelstein. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825.

16. Fischle, W., Y. Wang, and C. D. Allis. 2003. Binary switches and modification cassettes in histone biology and beyond. Nature 425:475–479.

17. Gostissa, M., A. Hengstermann, V. Fogal, P. Sandy, S. E. Schwarz, M. Scheffner, and G. Del Sal. 1999. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 18:6462–6471.

18. Gu, W., and R. Roeder. 1997. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606.

19. Harris, C. C. 1993. p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 262:1980–1981.

20. Hollstein, M., D. Sidransky, B. Vogelstein, and C. C. Harris. 1991. p53 mutations in human cancers. Science 253:49–53.

21. Huang, J., L. Perez-Burgos, B. J. Placek, R. Sengupta, M. Richter, J. A. Dorsey, S. Kubicek, S. Opravil, T. Jenuwein, and S. L. Berger. 2006. Repression of p53 activity by Smyd2-mediated methylation. Nature 444:629–632.

22. Hupp, T. R., D. W. Meek, C. A. Midgley, and D. P. Lane. 1992. Regulation of the specific DNA binding function of p53. Cell 71:875–886.

23. Imbriano, C., A. Gurtner, F. Cocchiarella, S. Di Agostino, V. Basile, M. Gostissa, M. Dobbelstein, G. Del Sal, G. Piaggio, and R. Mantovani. 2005. Direct p53 transcriptional repression: in vivo analysis of CCAAT-containing G2/M promoters. Mol. Cell. Biol. 25:3737–3751.

24. Kastan, M. B., O. Onyekwere, D. Sidransky, B. Vogelstein, and R. W. Craig. 1991. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51:6304–6311.

25. Kim, S. Y., A. Herbst, K. A. Tworkowski, S. E. Salghetti, and W. P. Tansey. 2003. Skp2 regulates Myc protein stability and activity. Mol. Cell 11:1177–1188.

26. Kouskouti, A., E. Scheer, A. Staub, L. Tora, and I. Talianidis. 2004. Genespecific modulation of TAF10 function by SET9-mediated methylation. Mol. Cell 14:175–182.

27. Kwek, S. S., J. Derry, A. L. Tyner, Z. Shen, and A. V. Gudkov. 2001. Functional analysis and intracellular localization of p53 modified by
SUMO-1. Oncogene 20:2587–2599.

28. Leonardo, A. D., S. P. Linke, K. Clarkin, and G. M. Wahl. 1994. DNA damage triggers a prolonged p53-dependent G1 arrest and a long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8:2540–2551.

29. Liu, G., T. Xia, and X. Chen. 2003. The activation domains, the proline-rich domain, and the C-terminal basic domain in p53 are necessary for acetylation of histones on the proximal p21 promoter and interaction with p300/CREB-binding protein. J. Biol. Chem. 278:17557–17565.

30. Lo, W. S., E. R. Gamache, K. W. Henry, D. Yang, L. Pillus, and S. L. Berger. 6768 IVANOV ET AL. MOL. CELL. BIOL. 2005. Histone H3 phosphorylation can promote TBP recruitment through distinct promoter-specific mechanisms. EMBO J. 24:997–1008.

31. Lo, W.-S., R. C. Trievel, J. R. Rojas, L. Duggan, J.-Y. Hsu, C. D. Allis, R. Marmorstein, and L. Berger. 2000. Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol. Cell 5:917–926.

32. Lowe, S. W., H. E. Ruley, T. Jacks, and D. E. Housman. 1993. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967.

33. Lowe, S. W., E. M. Schmitt, S. W. Smith, B. A. Osborne, and T. Jacks. 1993. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849.

34. Luo, J., M. Li, Y. Tang, M. Laszkowska, R. G. Roeder, and W. Gu. 2004. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc. Natl. Acad. Sci. USA 101:2259–2264.

35. Maltzman, W., and L. Czyzyk. 1984. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4:1689–1694.

36. Massague, J. 2004. G1 cell-cycle control and cancer. Nature 432:298–306.

37. Miyashita, T., S. Krajewski, M. Krajewska, H. G. Wang, H. K. Lin, D. A. Liebermann, B. Hoffman, and J. C. Reed. 1994. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9:1799–1805.

38. Morgunkova, A., and N. A. Barlev. 2006. Lysine methylation goes global. Cell Cycle 5:1308–1312.

39. Mujtaba, S., Y. He, L. Zeng, S. Yan, O. Plotnikova, Sachchidanand, R. Sanchez, N. J. Zeleznik-Le, Z. Ronai, and M. M. Zhou. 2004. Structural
mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol. Cell 13:251–263.

40. Nagashima, M., M. Shiseki, K. Miura, K. Hagiwara, S. P. Linke, R. Pedeux, X. W. Wang, J. Yokota, K. Riabowol, and C. C. Harris. 2001. DNA damageinducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. Proc. Natl. Acad. Sci. USA 98:9671–9676.

41. Nishioka, K., S. Chuikov, K. Sarma, H. Erdjument-Bromage, C. D. Allis, P. Tempst, and D. Reinberg. 2002. Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev. 16:479–489.

42. Nishioka, K., J. C. Rice, K. Sarma, H. Erdjument-Bromage, J. Werner, Y. Wang, S. Chuikov, P. Valenzuela, P. Tempst, R. Steward, J. T. Lis, C. D. Allis, and D. Reinberg. 2002. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell 9:1201–1213.

43. Polyak, K., Y. Xia, J. L. Zweier, K. W. Kinzler, and B. Vogelstein. 1997. A model for p53-induced apoptosis. Nature 389:300–305.

44. Saito, S., H. Yamaguchi, Y. Higashimoto, C. Chao, Y. Xu, A. J. Fornace, Jr., E. Appella, and C. W. Anderson. 2003. Phosphorylation site interdependence of human p53 posttranslational modifications in response to stress. J. Biol. Chem. 278:37536–37544.

45. Sakaguchi, K., J. E. Herrera, S. Saito, T. Miki, M. Bustin, A. Vassilev, C. W. Anderson, and E. Appella. 1998. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 12:2831–2841.

46. Sakaguchi, K., H. Sakamoto, D. Xie, J. W. Erickson, M. S. Lewis, C. W. Anderson, and E. Appella. 1997. Effect of phosphorylation on tetramerization of the tumor suppressor protein p53. J. Protein Chem. 16:553–556.

47. Salghetti, S. E., A. A. Caudy, J. G. Chenoweth, and W. P. Tansey. 2001. Regulation of transcriptional activation domain function by ubiquitin. Science 293:1651–1653.

48. Shah, G., R. Ghosh, P. A. Amstad, and P. A. Cerutti. 1993. Mechanism of induction of c-fos by ultraviolet B (290–320 nm) in mouse JB6 epidermal cells. Cancer Res. 53:38–45.

49. Sheikh, M. S., T. F. Burns, Y. Huang, G. S. Wu, S. Amundson, K. S. Brooks, A. J. Fornace, Jr., and W. S. el-Deiry. 1998. p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res. 58:1593–1598.

50. Shi, X., T. Hong, K. L. Walter, M. Ewalt, E. Michishita, T. Hung, D. Carney, P. Pena, F. Lan, M. R. Kaadige, N. Lacoste, C. Cayrou, F. Davrazou, A. Saha, B. R. Cairns, D. E. Ayer, T. G. Kutateladze, Y. Shi, J. Cote, K. F. Chua, and O. Gozani. 2006. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442:96–99.

51. Shiseki, M., M. Nagashima, R. M. Pedeux, M. Kitahama-Shiseki, K. Miura, S. Okamura, H. Onogi, Y. Higashimoto, E. Appella, J. Yokota, and C. C. Harris. 2003. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 63:2373–2378.

52. Su, L., Y. Sai, R. Fan, S. W. Thurston, D. P. Miller, W. Zhou, J. C. Wain, T. J. Lynch, G. Liu, and D. C. Christiani. 2003. P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21. Lung Cancer 40:259–266.

53. Taylor, W. R., and G. R. Stark. 2001. Regulation of the G2/M transition by p53. Oncogene 20:1803–1815.

54. Wang, C., A. Ivanov, L. Chen, W. J. Fredericks, E. Seto, F. J. Rauscher III, and J. Chen. 2005. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 24:3279–3290.

55. Wang, H., R. Cao, L. Xia, H. Erdjument-Bromage, C. Borchers, P. Tempst, and Y. Zhang. 2001. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol. Cell 8:1207–1217.

56. Waterman, M. J., E. S. Stavridi, J. L. Waterman, and T. D. Halazonetis. 1998. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nat. Genet. 19:175–178.

57. Willis, S. N., and J. M. Adams. 2005. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17:617–625.

58. Wysocka, J., T. Swigut, H. Xiao, T. A. Milne, S. Y. Kwon, J. Landry, M. Kauer, A. J. Tackett, B. T. Chait, P. Badenhorst, C. Wu, and C. D. Allis. 2006. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodeling. Nature 442:86–90.

59. Xu, Y. 2003. Regulation of p53 responses by posttranslational modifications. Cell Death Differ. 10:400–403.

60. Yun, J., H. D. Chae, H. E. Choy, J. Chung, H. S. Yoo, M. H. Han, and D. Y. Shin. 1999. p53 negatively regulates cdc2 transcription via the CCAATbinding NF-Y transcription factor. J. Biol. Chem. 274:29677–29682.

61. Zegerman, P., B. Canas, D. Pappin, and T. Kouzarides. 2002. Histone H3 lysine 4 methylation disrupts binding of nucleosome remodeling and deacetylase (NuRD) repressor complex. J. Biol. Chem. 277:11621–11624.

62. Zhao, R., K. Gish, M. Murphy, Y. Yin, D. Notterman, W. H. Hoffman, E. Tom, D. H. Mack, and A. J. Levine. 2000. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14:981–993.

Прочитано 3996 раз
Оцените материал
(0 голосов)
Опубликовано в СТАТЬИ
Авторизуйтесь, чтобы получить возможность оставлять комментарии


Управление научных исследований СПбГТИ (ТУ)

Горячие новости

Приборное оснащение лаборатории

Rambler's Top100
//'+ 'Рейтинг@Mail.ru<\/a><\/p>');})(window,navigator,document);//]]>