Molecules and Cells

  • 제26권4호
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  • Pages.350-355
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  • 2008
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지

Genetic Screen for Genes Involved in Chk2 Signaling in Drosophila

  • 투고 : 2008.03.13
  • 심사 : 2008.06.20
  • 발행 : 2008.10.31
⟨ 이전 논문 다음 논문 ⟩

초록

Chk2 is a well characterized protein kinase with key roles in the DNA damage response. Chk2 is activated by phosphorylation following DNA damage, and relays that signal to various substrate proteins to induce cell cycle arrest, DNA repair, and apoptosis. In order to identify novel components of the Chk2 signaling pathway in Drosophila, we screened 2,240 EP misexpression lines for dominant modifiers of an adult rough eye phenotype caused by Chk2 overexpression in postmitotic cells of the eye imaginal disc. The rough eye phenotype was suppressed by mutation of the ATM kinase, a well-described activator of Chk2. Twenty-five EP modifiers were identified (three enhancers and 22 suppressors), none of which correspond to previously known components of Chk2 signaling. Three EPs caused defects in G2 arrest after irradiation with incomplete penetrance when homozygous, and are likely directly involved in the response to DNA damage. Possible roles for these modifiers in the DNA damage response and Chk2 signaling are discussed.

키워드

과제정보

연구 과제 주관 기관 : Ministry of Science and Technology

참고문헌

  1. Aihara, H., Nakagawa, T., Yasui, K., Ohta, T., Hirose, S., Dhomae, N., Takio, K., Kaneko, M., Takeshima, Y., Muramatsu, M., et al. (2004). Nucleosomal histone kinase-1 phosphorylates H2A Thr 119 during mitosis in the early aêçëçéÜáä- embryo. Genes Dev. 18, 877-888 https://doi.org/10.1101/gad.1184604
  2. Anholt, R.R., Dilda, C.L., Chang, S., Fanara, J.J., Kulkarni, N.H., Ganguly, I., Rollmann, S.M., Kamdar, K.P., and Mackay, T.F. (2003). The genetic architecture of odor-guided behavior in Drosophila : epistasis and the transcriptome. Nat. Genet. 35, 180- 184 https://doi.org/10.1038/ng1240
  3. Antoni, L., Sodha, N., Collins, I., and Garrett, M.D. (2007). CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat. Rev. Cancer 7, 925-936
  4. Beidler, D.R., Tewari, M., Friesen, P.D., Poirier, G., and Dixit, V.M. (1995). The baculovirus p35 protein inhibits Fas- and tumor necrosis factor-induced apoptosis. J. Biol. Chem. 270 16526-16528 https://doi.org/10.1074/jbc.270.28.16526
  5. Bienz, M. (2006). The PHD finger, a nuclear protein-interaction domain. Trends Biochem. Sci. 31, 35-40 https://doi.org/10.1016/j.tibs.2005.11.001
  6. Bray, S.J. (1997). Expression and function of enhancer of split bHLH proteins during Drosophila neurogenesis. Perspect. Dev. Neurobiol. 4, 313-323
  7. Brodsky, M.H., Nordstrom, W., Tsang, G., Kwan, E., Rubin, G.M., and Abrams, J.M. (2000). Drosophila p53 binds a damage response element at the reaper locus. Cell 101, 103-113 https://doi.org/10.1016/S0092-8674(00)80627-3
  8. Brodsky, M.H., Weinert, B.T., Tsang, G., Rong, Y.S., McGinnis, N.M., Golic, K.G., Rio, D.C., and Rubin, G.M. (2004). Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage. Mol. Cell. Biol. 24, 1219-1231 https://doi.org/10.1128/MCB.24.3.1219-1231.2004
  9. Dansereau, D.A., Lunke, M.D., Finkielsztein, A., Russell, M.A., and Brook, W.J. (2002). Hephaestus encodes a polypyrimidine tract binding protein that regulates Notch signalling during wing development in Drosophila melanogaster. Development 129, 5553-5566 https://doi.org/10.1242/dev.00153
  10. Davis, R.L., and Turner, D.L. (2001). Vertebrate hairy and enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20, 8342-8357 https://doi.org/10.1038/sj.onc.1205094
  11. Dubnau, J., Chiang, A.S., Grady, L., Barditch, J., Gossweiler, S., McNeil, J., Smith, P., Buldoc, F., Scott, R., Certa, U., et al. (2003). The staufen/pumilio pathway is involved in Drosophila long-term memory. Curr. Biol. 13, 286-296 https://doi.org/10.1016/S0960-9822(03)00064-2
  12. Fischer, A., and Gessler, M. (2007). Delta-Notch--and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res. 35, 4583-4596 https://doi.org/10.1093/nar/gkm477
  13. Garcia-Blanco, M.A., Jamison, S.F., and Sharp, P.A. (1989). Identification and purification of a 62,000-dalton protein that binds specifically to the polypyrimidine tract of introns. Genes Dev. 3, 1874-1886 https://doi.org/10.1101/gad.3.12a.1874
  14. Goshima, G., Wollman, R., Goodwin, S.S., Zhang, N., Scholey, J.M., Vale, R.D., and Stuurman, N. (2007). Genes required for mitotic spindle assembly in Drosophila S2 cells. Science 316, 417-421 https://doi.org/10.1126/science.1141314
  15. He, X., Pool, M., Darcy, K.M., Lim, S.B., Auersperg, N., Coon, J.S., and Beck, W.T. (2007). Knockdown of polypyrimidine tractbinding protein suppresses ovarian tumor cell growth and invasiveness in vitro. Oncogene 26, 4961-4968 https://doi.org/10.1038/sj.onc.1210307
  16. Huang, A.M., and Rubin, G.M. (2000). A misexpression screen identifies genes that can modulate RAS1 pathway signaling in Drosophila melanogaster. Genetics 156, 1219-1230
  17. Hyun, J., Becam, I., Yanicostas, C., and Bohmann, D. (2006). Control of G2/M transition by Drosophila Fos. Mol. Cell. Biol. 26, 8293-8302 https://doi.org/10.1128/MCB.02455-05
  18. Klose, R.J., Kallin, E.M., and Zhang, Y. (2006). JmjC-domaincontaining proteins and histone demethylation. Nat. Rev. Genet. 7, 715-727 https://doi.org/10.1038/nrg1945
  19. Kulkarni, A., and Wilson, D.M. 3rd. (2008). The involvement of DNA-damage and -repair defects in neurological dysfunction. Am. J. Hum. Genet 82, 539-566 https://doi.org/10.1016/j.ajhg.2008.01.009
  20. Nichols, R.J., and Traktman, P. (2004). Characterization of three paralogous members of the mammalian vaccinia related kinase family. J. Biol. Chem. 279, 7934-7946 https://doi.org/10.1074/jbc.M310813200
  21. Ollmann, M., Young, L.M., Di Como, C.J., Karim, F., Belvin, M., Robertson, S., Whittaker, K., Demsky, M., Fisher, W.W., Buchman, A., et al. (2000). Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101, 91-101 https://doi.org/10.1016/S0092-8674(00)80626-1
  22. Pena-Rangel, M.T., Rodriguez, I., and Riesgo-Escovar, J.R. (2002). A misexpression study examining dorsal thorax formation in Drosophila melanogaster. Genetics 160, 1035-1050
  23. Reeves, N., and Posakony, J.W. (2005). Genetic programs activated by proneural proteins in the developing Drosophila PNS. Dev. Cell 8, 413-425 https://doi.org/10.1016/j.devcel.2005.01.020
  24. Rorth, P. (1996). A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. Proc. Natl. Acad. Sci. USA 93, 12418-12422
  25. Rorth, P., Szabo, K., Bailey, A., Laverty, T., Rehm, J., Rubin, G.M., Weigmann, K., Milán, M., Benes, V., and Ansorge, W. (1998). Systematic gain-of-function genetics in Drosophila. Development 125, 1049-1057
  26. Sancar, A., Lindsey-Boltz, L.A., Unsal-Kaçmaz, K., and Linn, S. (2004). Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39-85 https://doi.org/10.1146/annurev.biochem.73.011303.073723
  27. Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B., and Cavalli, G. (2007). Genome regulation by polycomb and trithorax proteins. Cell 128, 735-745 https://doi.org/10.1016/j.cell.2007.02.009
  28. Schultz, J., Milpetz, F., Bork, P., and Ponting, C.P. (1998). SMART, a simple modular architecture research tool: identification of signaling domains. Proc. Natl. Acad. Sci. USA 95, 5857-5864
  29. Schulz, C., Kiger, A.A., Tazuke, S.I., Yamashita, Y.M., Pantalena- Filho, L.C., Jones, D.L., Wood, C.G., and Fuller, M.T. (2004). A misexpression screen reveals effects of bag-of-marbles and TGF beta class signaling on the Drosophila male germ-line stem cell lineage. Genetics 167, 707-723 https://doi.org/10.1534/genetics.103.023184
  30. Song, Y.H. (2005). Drosophila melanogaster: a model for the study of DNA damage checkpoint response. Mol. Cells 19, 167-179
  31. Song, Y.H., Mirey, G., Betson, M., Haber, D.A., and Settleman, J. (2004). The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development. Curr. Biol. 14, 1354-1359 https://doi.org/10.1016/j.cub.2004.06.064
  32. Spradling, A.C., Stern, D.M., Kiss, I., Roote, J., Laverty, T., and Rubin, G.M. (1995). Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc. Natl. Acad. Sci. USA 92, 10824-10830
  33. Staalesen, V., Falck, J., Geisler, S., Bartkova, J., Borresen-Dale, A.L., Lukas, J., Lillehaug, J.R., Bartek, J., and Lonning, P.E. (2004). Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene 23, 8535-8544 https://doi.org/10.1038/sj.onc.1207928
  34. Stevens, C., Smith, L., and La Thangue, N.B. (2003). Chk2 activates E2F-1 in response to DNA damage. Nat. Cell Biol. 5, 401- 409 https://doi.org/10.1038/ncb974
  35. Terry, N.A., Tulina, N., Matunis, E., and DiNardo, S. (2006). Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev. Biol. 294, 246-257 https://doi.org/10.1016/j.ydbio.2006.02.048
  36. Tschape, J.A., Hammerschmied, C., Muhlig-Versen, M., Athenstaedt, K., Daum, G., and Kretzschmar, D. (2002). The neurodegeneration mutant lochrig interferes with cholesterol homeostasis and Appl processing. EMBO J. 21, 6367-6376 https://doi.org/10.1093/emboj/cdf636
  37. Valbuena, A., Vega, F.M., Blanco, S., and Lazo, P.A. (2004). p53 Stabilization and accumulation induced by human vacciniarelated kinase 1. Mol. Cell. Biol. 24, 10366-10380 https://doi.org/10.1128/MCB.24.23.10366-10380.2004
  38. Wilson, R.J., Goodman, J.L., Strelets, V.B.; FlyBase Consortium. (2008). FlyBase: integration and improvements to query tools. Nucleic Acids Res. 36, D588-593 https://doi.org/10.1093/nar/gkm930
  39. Xu, J., and Du, W. (2003). Drosophila chk2 plays an important role in a mitotic checkpoint in syncytial embryos. FEBS Lett. 545, 209-212 https://doi.org/10.1016/S0014-5793(03)00536-2
  40. Xu, J., Xin, S., and Du, W. (2001). Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. FEBS Lett. 508, 394-398 https://doi.org/10.1016/S0014-5793(01)03103-9
  41. Yang, S., Kuo, C., Bisi, J.E., and Kim, M.K. (2002). PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat. Cell Biol. 4, 865-870 https://doi.org/10.1038/ncb869
  42. Yu, X., Alder, J.K., Chun, J.H., Friedman, A.D., Heimfeld, S., Cheng, L., and Civin, C.I. (2006). HES1 inhibits cycling of hematopoietic progenitor cells via DNA binding. Stem Cells 24, 876-888 https://doi.org/10.1634/stemcells.2005-0598