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Gene Review

RAD9  -  Rad9p

Saccharomyces cerevisiae S288c

Synonyms: DNA repair protein RAD9, YD9934.02C, YDR217C
 
 
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Disease relevance of RAD9

  • In yeast, TDP mutation confers a 1000-fold hypersensitivity to camptothecin in the presence of an additional mutation of RAD9 gene [Pouliot, J.J., Yao, K.C., Robertson, C.A. & Nash, H.A. (1999) Science 286, 552-555] [1].
  • It is demonstrated that the pronounced G1 arrest observed in yeast after hyperthermia treatment or exposure to paraquat-generated superoxide radicals does not depend on a functional RAD9 gene [2].
  • In the present study, semiquantitative reverse transcription-PCR showed that Rad9 mRNA levels were up-regulated in 52.1% (25 of 48) of breast tumors, and this up-regulation correlated with tumor size (P = 0.037) and local recurrence (P = 0.033) [3].
 

High impact information on RAD9

  • Surprisingly, both yKu and the chromatin-associated Rap1 and SIR proteins are released from telomeres in a RAD9-dependent response to DNA damage. yKu is recruited rapidly to double-strand cuts, while low levels of SIR proteins are detected near cleavage sites at later time points [4].
  • This adaptation-defective phenotype was entirely relieved by deletion of RAD9, a gene required for the G2/M DNA damage checkpoint arrest [5].
  • In wild-type cells, elimination of a telomere caused a RAD9-mediated cell cycle arrest, indicating that telomeres help cells to distinguish intact chromosomes from damaged DNA [6].
  • Curiously, the mitosis-specific checkpoint gene RAD9 is not required for meiotic arrest of dmc1 mutants [7].
  • In the budding yeast, for example, the RAD9 gene product is required to delay progression into mitosis in response to DNA damage [8].
 

Biological context of RAD9

 

Anatomical context of RAD9

  • RAD9, which is necessary for the DNA damage checkpoint, is required for the preanaphase arrest of sid2-1 sic1 Delta cells [14].
  • However, efficient DNA repair can occur in irradiated rad9 cells if irradiated cells are blocked for several hours in G2 by treatment with a microtubule poison [15].
  • Rates of survival and checkpoint delay of the mutants after ultraviolet (UV) irradiation were essentially equivalent to those of rad9Delta (null) cells, demonstrating that the BRCT domain is required for Rad9 function [16].
  • Treatment of MCF-7 cell line with 5'-aza-2'-deoxycytidine reduced Rad9 mRNA expression and also increased binding of Sp3 to the demethylated intron 2 region [3].
 

Associations of RAD9 with chemical compounds

  • We propose that selenite treatment leads to DNA damage inducing the RAD9-dependent cell cycle arrest [17].
  • Interruption of the RAD9 gene, which is involved in DNA-damage-induced cell cycle arrest, had no affect on cisplatin cytotoxicity [18].
  • In addition, rad9 rad18 is no more sensitive to MMS than the rad18 single mutant, suggesting that rad9 plays a role within the PRR pathway [19].
  • Epistatic analysis showed that rad9 is synergistic to both mms2 and rev3 with respect to killing by methyl methanesulfonate (MMS), and the triple mutant is nearly as sensitive as the rad18 single mutant [19].
  • These results indicate that the lysine-dependent function of histone H4 is required for the maintenance of genome integrity, and that DNA damage resulting from the loss of this function activates the RAD9-dependent G2/M checkpoint pathway [20].
 

Physical interactions of RAD9

  • Since the phosphorylated form of Rad9p appears capable of interacting stably with Rad53p in vivo, this phosphorylation response likely controls checkpoint signaling by Rad9p [10].
 

Enzymatic interactions of RAD9

 

Regulatory relationships of RAD9

 

Other interactions of RAD9

 

Analytical, diagnostic and therapeutic context of RAD9

  • We find that exposure of RAD9 cells to X-irradiation early in meiosis prevents sporulation, arresting the cells at a stage prior to premeiotic DNA replication. rad9 meiotic cells are much less responsive to X-irradiation damage, completing sporulation after treatment with doses sufficient to cause arrest of RAD9 strains [29].
  • Northern blot analysis demonstrated that RAD9 controls the DNA damage-specific induction of a large 'regulon' of repair, replication and recombination genes [30].
  • Cloning and sequence analysis of the Saccharomyces cerevisiae RAD9 gene and further evidence that its product is required for cell cycle arrest induced by DNA damage [31].
  • Upon transfer from the restrictive to the permissive temperature, a larger proportion of the cdc9 cells than of the cdc9 rad9 delta cells forms viable colonies, indicating that RAD9-mediated cell cycle arrest allows for proper ligation of DNA breaks before the entry of cells into mitosis [31].
  • Surface plasmon resonance analysis showed that a pThr peptide containing this motif, (188)SLEV(pT)EADATFVQ(200) from Rad9, binds to FHA1 with a K(d) value of 0.36 microM [32].

References

  1. Kinetic studies of human tyrosyl-DNA phosphodiesterase, an enzyme in the topoisomerase I DNA repair pathway. Cheng, T.J., Rey, P.G., Poon, T., Kan, C.C. Eur. J. Biochem. (2002) [Pubmed]
  2. Hyperthermia and paraquat-induced G1 arrest in the yeast Saccharomyces cerevisiae is independent of the RAD9 gene. Nunes, E., Siede, W. Radiation and environmental biophysics. (1996) [Pubmed]
  3. The cell cycle checkpoint gene Rad9 is a novel oncogene activated by 11q13 amplification and DNA methylation in breast cancer. Cheng, C.K., Chow, L.W., Loo, W.T., Chan, T.K., Chan, V. Cancer Res. (2005) [Pubmed]
  4. Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Martin, S.G., Laroche, T., Suka, N., Grunstein, M., Gasser, S.M. Cell (1999) [Pubmed]
  5. CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Toczyski, D.P., Galgoczy, D.J., Hartwell, L.H. Cell (1997) [Pubmed]
  6. Loss of a yeast telomere: arrest, recovery, and chromosome loss. Sandell, L.L., Zakian, V.A. Cell (1993) [Pubmed]
  7. A meiotic recombination checkpoint controlled by mitotic checkpoint genes. Lydall, D., Nikolsky, Y., Bishop, D.K., Weinert, T. Nature (1996) [Pubmed]
  8. The wee1 protein kinase is required for radiation-induced mitotic delay. Rowley, R., Hudson, J., Young, P.G. Nature (1992) [Pubmed]
  9. RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae. Navas, T.A., Sanchez, Y., Elledge, S.J. Genes Dev. (1996) [Pubmed]
  10. MEC1-dependent phosphorylation of Rad9p in response to DNA damage. Emili, A. Mol. Cell (1998) [Pubmed]
  11. The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage. Vialard, J.E., Gilbert, C.S., Green, C.M., Lowndes, N.F. EMBO J. (1998) [Pubmed]
  12. RAD9 and RAD24 define two additive, interacting branches of the DNA damage checkpoint pathway in budding yeast normally required for Rad53 modification and activation. de la Torre-Ruiz, M.A., Green, C.M., Lowndes, N.F. EMBO J. (1998) [Pubmed]
  13. RAD9, RAD17, and RAD24 are required for S phase regulation in Saccharomyces cerevisiae in response to DNA damage. Paulovich, A.G., Margulies, R.U., Garvik, B.M., Hartwell, L.H. Genetics (1997) [Pubmed]
  14. Mutations in SID2, a novel gene in Saccharomyces cerevisiae, cause synthetic lethality with sic1 deletion and may cause a defect during S phase. Jacobson, M.D., Muñoz, C.X., Knox, K.S., Williams, B.E., Lu, L.L., Cross, F.R., Vallen, E.A. Genetics (2001) [Pubmed]
  15. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Weinert, T.A., Hartwell, L.H. Science (1988) [Pubmed]
  16. The BRCT domain of the S. cerevisiae checkpoint protein Rad9 mediates a Rad9-Rad9 interaction after DNA damage. Soulier, J., Lowndes, N.F. Curr. Biol. (1999) [Pubmed]
  17. Identification of genes affecting selenite toxicity and resistance in Saccharomyces cerevisiae. Pinson, B., Sagot, I., Daignan-Fornier, B. Mol. Microbiol. (2000) [Pubmed]
  18. The HMG-domain protein Ixr1 blocks excision repair of cisplatin-DNA adducts in yeast. McA'Nulty, M.M., Lippard, S.J. Mutat. Res. (1996) [Pubmed]
  19. DNA damage checkpoints are involved in postreplication repair. Barbour, L., Ball, L.G., Zhang, K., Xiao, W. Genetics (2006) [Pubmed]
  20. Histone H4 and the maintenance of genome integrity. Megee, P.C., Morgan, B.A., Smith, M.M. Genes Dev. (1995) [Pubmed]
  21. Association of Rad9 with double-strand breaks through a Mec1-dependent mechanism. Naiki, T., Wakayama, T., Nakada, D., Matsumoto, K., Sugimoto, K. Mol. Cell. Biol. (2004) [Pubmed]
  22. Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. Sun, Z., Hsiao, J., Fay, D.S., Stern, D.F. Science (1998) [Pubmed]
  23. Mec1 and Rad53 inhibit formation of single-stranded DNA at telomeres of Saccharomyces cerevisiae cdc13-1 mutants. Jia, X., Weinert, T., Lydall, D. Genetics (2004) [Pubmed]
  24. Saccharomyces cerevisiae RAD53 (CHK2) but not CHK1 is required for double-strand break-initiated SCE and DNA damage-associated SCE after exposure to X rays and chemical agents. Fasullo, M., Dong, Z., Sun, M., Zeng, L. DNA Repair (Amst.) (2005) [Pubmed]
  25. Cdc20, a beta-transducin homologue, links RAD9-mediated G2/M checkpoint control to mitosis in Saccharomyces cerevisiae. Lim, H.H., Surana, U. Mol. Gen. Genet. (1996) [Pubmed]
  26. Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13. Grandin, N., Reed, S.I., Charbonneau, M. Genes Dev. (1997) [Pubmed]
  27. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Garvik, B., Carson, M., Hartwell, L. Mol. Cell. Biol. (1995) [Pubmed]
  28. Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair. Weinert, T.A., Kiser, G.L., Hartwell, L.H. Genes Dev. (1994) [Pubmed]
  29. Stage-specific effects of X-irradiation on yeast meiosis. Thorne, L.W., Byers, B. Genetics (1993) [Pubmed]
  30. A novel role for the budding yeast RAD9 checkpoint gene in DNA damage-dependent transcription. Aboussekhra, A., Vialard, J.E., Morrison, D.E., de la Torre-Ruiz, M.A., Cernáková, L., Fabre, F., Lowndes, N.F. EMBO J. (1996) [Pubmed]
  31. Cloning and sequence analysis of the Saccharomyces cerevisiae RAD9 gene and further evidence that its product is required for cell cycle arrest induced by DNA damage. Schiestl, R.H., Reynolds, P., Prakash, S., Prakash, L. Mol. Cell. Biol. (1989) [Pubmed]
  32. Structure of the FHA1 domain of yeast Rad53 and identification of binding sites for both FHA1 and its target protein Rad9. Liao, H., Yuan, C., Su, M.I., Yongkiettrakul, S., Qin, D., Li, H., Byeon, I.J., Pei, D., Tsai, M.D. J. Mol. Biol. (2000) [Pubmed]
 
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