Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation

详细信息    查看全文

• 作者：Junya Kobayashi (1)
  Akihiro Kato (1)
  Yosuke Ota (1)
  Reiko Ohba (1) (2)
  Kenshi Komatsu (1)
  
• 刊名：Molecular Cancer
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：9
• 期：1
• 全文大小：2111KB
• 参考文献：1. Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K: NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain. / Curr Biol 2002, 12:1846-851. CrossRef
  2. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A: Genomic instability in mice lacking histone H2AX. / Science 2002, 296:922-27. CrossRef
  3. Stucki M, Jackson S: gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. / DNA Repair 2006, 5:534-43. CrossRef
  4. Kobayashi J, Antoccia A, Tauchi H, Matsuura S, Komatsu K: NBS1 and its functional role in the DNA damage response. / DNA Repair 2004, 3:855-61. CrossRef
  5. Paull TT, Rogakou E, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM: A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. / Curr Biol 2000, 10:886-95. CrossRef
  6. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ: MDC1 is a mediator of the mammalian DNA damage checkpoint. / Nature 2003, 421:961-66. CrossRef
  7. Kobayashi J, Tauchi H, Chen B, Burma S, Tashiro S, Matsuura S, Tanimoto K, Chen DJ, Komatsu K: Histone H2AX participates the DNA damage-induced ATM activation through interaction with NBS1. / Biochem Biophys Res Commun 2009, 380:752-57. CrossRef
  8. Xie A, Puget N, Shim I, Odate S, Jarzyna I, Bassing CH, Alt FW, Scully R: Control of sister chromatid recombination by histone H2AX. / Molecular Cell 2007, 16:1017-025. CrossRef
  9. Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW: Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. / Cell 2003, 114:359-70. CrossRef
  10. Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A: H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. / Cell 2003, 114:371-83. CrossRef
  11. Paull TT, Gellert M: The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. / Mol Cell 1998, 1:969-79. CrossRef
  12. Paull TT, Gellert M: Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. / Genes Dev 1999, 13:1276-288. CrossRef
  13. Dolganov GM, Maser R, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH: Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair. / Mol Cell Biol 1996, 16:4832-841.
  14. Johzuka K, Ogawa H: Interaction of Mre11 and Rad50: two proteins required for DNA repair and meiosis-specific double-strand break formation in Saccharomyces cerevisiae. / Genetics 1995, 139:1521-532.
  15. Stewart GS, Maser R, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM: The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. / Cell 1999, 10:577-87. CrossRef
  16. Pitts SA, Kullar H, Stankovic T, Stewart GS, Last JI, Bedenham T, Armstrong SJ, Piane M, Chessa L, Taylor AM, Byrd PJ: hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay. / Hum Mol Genet 2001, 10:1155-162. CrossRef
  17. Delia D, Piane M, Buscemi G, Savio C, Palmeri S, Lulli P, Carlessi L, Fontanella E, Chessa L: MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. / Hum Mol Genet 2004, 13:2155-163. CrossRef
  18. Yamaguchi-Iwai Y, Sonoda E, Sasaki MS, Morrison C, Haraguchi T, Hiraoka Y, Yamashita YM, Yagi T, Takata M, Price C, Kakazu N, Takeda S: Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells. / EMBO J 1999, 18:6619-629. CrossRef
  19. Tauchi H, Kobayashi J, Morishima K, van Gent DC, Shiraishi T, Verkaik NS, vanHeems D, Ito E, Nakamura A, Sonoda E, Takata M, Takeda S, Matsuura S, Komatsu K: Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. / Nature 2002, 420:93-8. CrossRef
  20. Sakamoto S, Iijima K, Mochizuki D, Nakamura K, Teshigawara K, Kobayashi J, Matsuura S, Tauchi H, Komatsu K: Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions. / Oncogene 2007, 26:6002-009. CrossRef
  21. Burchmore RJ, Ogbunude P, Enanga B, Barrett MP: Chemotherapy of human African trypanosomiasis. / Curr Pharm Des 2002, 8:256-67. CrossRef
  22. Bakshi RP, Shapiro T: DNA topoisomerases as targets for antiprotozoal therapy. / Mini Rev Med Chem 2003, 3:597-08. CrossRef
  23. Wilson WD, Tanious F, Mathis A, Tevis D, Hall JE, Boykin DW: Antiparasitic compounds that target DNA. / Biochimie 2008, 90:999-014. CrossRef
  24. Hildebrandt E, Boykin D, Kumar A, Tidwell RR, Dykstra CC: Identification and characterization of an endo/exonuclease in Pneumocystis carinii that is inhibited by dicationic diarylfurans with efficacy against Pneumocystis pneumonia. / J Eukaryot Microbiol 1998, 45:112-21. CrossRef
  25. Bornstein RS, Yarbro J: An evaluation of the mechanism of action of pentamidine isethionate. / J Surg Oncol 1970, 2:393-98. CrossRef
  26. Chow TY, Alaoui-Jamali M, Yeh C, Yuen L, Griller D: The DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer. / Mol Cancer Ther 2004, 3:911-19. CrossRef
  27. Falck J, Coates J, Jackson SP: Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. / Nature 2005, 434:605-11. CrossRef
  28. Potts PR, Porteus M, Yu H: Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks. / EMBO J 2006, 25:3377-388. CrossRef
  29. Iijima K, Ohara M, Seki R, Tauchi H: Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage. / J Radiat Res 2008, 49:451-64. CrossRef
  30. Pierce AJ, Jasin M: Measuring recombination proficiency in mouse embryonic stem cells. / Methods Mol Biol 2005, 291:373-84.
  31. Murr R, Loizou J, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z: Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. / Nat Cell Biol 2006, 8:91-9. CrossRef
  32. Ikura T, Ogryzko V, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y: Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. / Cell 2000, 102:463-73. CrossRef
  33. Ikura T, Tashiro S, Kakino A, Shima H, Jacob N, Amunugama R, Yoder K, Izumi S, Kuraoka I, Tanaka K, Kimura H, Ikura M, Nishikubo S, Ito T, Muto A, Miyagawa K, Takeda S, Fishel R, Igarashi K, Kamiya K: DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. / Mol Cell Biol 2007, 27:7028-040. CrossRef
  34. Tang Y, Luo J, Zhang W, Gu W: Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. / Mol Cell 2006, 24:827-39. CrossRef
  35. Choudhury SA, Asefa B, Webb A, Ramotar D, Chow TY: Functional and genetic analysis of the Saccharomyces cerevisiae RNC1/TRM2: evidences for its involvement in DNA double-strand break repair. / Mol Cell Biochem 2007, 300:215-26. CrossRef
  36. Tamburini BA, Tyler J: Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. / Mol Cell Biol 2005, 25:4903-913. CrossRef
  37. Downs JA, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, Bouchard N, Kron SJ, Jackson SP, C?té J: Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. / Mol Cell 2004, 16:979-90. CrossRef
  38. Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, Elliott P, Borisy AA, Keith CT: The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. / Cancer Res 2007, 67:11359-1367. CrossRef
  39. Singh G, Dey C: Induction of apoptosis-like cell death by pentamidine and doxorubicin through differential inhibition of topoisomerase II in arsenite-resistant L. donovani. / Acta Trop 2007, 103:172-85. CrossRef
  40. Ito A, Tauchi H, Kobayashi J, Morishima K, Nakamura A, Hirokawa Y, Matsuura S, Ito K, Komatsu K: Expression of full-length NBS1protein restores normal radiation responses in cells from Nijmegen breakage syndrome patients. / Biochem Biophys Res Commun 1999, 265:716-21. CrossRef
  41. Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G: Nuclear retention of ATM at sites of DNA double strand breaks. / J Biol Chem 2002, 276:38224-8230.
  42. Mansour WY, Schumacher S, Rosskopf R, Rhein T, Schmidt-Petersen F, Gatzemeier F, Haag F, Borgmann K, Willers H, Dahm-Daphi J: Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks. / Nucleic Acids Res 2008, 36:4088-098. CrossRef
  
• 作者单位：Junya Kobayashi (1)
  Akihiro Kato (1)
  Yosuke Ota (1)
  Reiko Ohba (1) (2)
  Kenshi Komatsu (1)
  
  1. Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, 606-8501, Japan
  2. National Institute of Genetics, Yata 1111, Mishima, Sizuoka, 411-8540, Japan
  
• ISSN：1476-4598

文摘

Background MRE11 is an important nuclease which functions in the end-resection step of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). As MRE11-deficient ATLD cells exhibit hyper radio-sensitivity and impaired DSB repair, MRE11 inhibitors could possibly function as potent radio-sensitizers. Therefore, we investigated whether a bisbenzamidine derivative, pentamidine, which can inhibit endoexonuclease activity, might influence DSB-induced damage responses via inhibition of MRE11. Results We first clarified that pentamidine inhibited MRE11 nuclease activity and also reduced ATM kinase activity in vitro. Pentamidine increased the radio-sensitivity of HeLa cells, suggesting that this compound could possibly influence DNA damage response factors in vivo. Indeed, we found that pentamidine reduced the accumulation of γ-H2AX, NBS1 and phospho-ATM at the sites of DSBs. Furthermore, pentamidine decreased HR activity in vivo. Pentamidine was found to inhibit the acetylation of histone H2A which could contribute both to inhibition of IR-induced focus formation and HR repair. These results suggest that pentamidine might exert its effects by inhibiting histone acetyltransferases. We found that pentamidine repressed the activity of Tip60 acetyltransferase which is known to acetylate histone H2A and that knockdown of Tip60 by siRNA reduced HR activity. Conclusion These results indicate that inhibition of Tip60 as well as hMRE11 nuclease by pentamidine underlies the radiosensitizing effects of this compound making it an excellent sensitizer for radiotherapy or chemotherapy.