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Gene Review

RAD53  -  Rad53p

Saccharomyces cerevisiae S288c

Synonyms: CHEK2 homolog, LSD1, MEC2, P2588, SAD1, ...
 
 
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Disease relevance of RAD53

  • MDT1 overexpression is synthetically lethal with a rad53 deletion, whereas mdt1 deletion partially suppresses the DNA damage hypersensitivity of checkpoint-compromised strains and generally improves DNA damage tolerance [1].
 

High impact information on RAD53

 

Chemical compound and disease context of RAD53

  • We found that Ccr4 cooperated with the Dun1 branch of the replication checkpoint, such that ccr4Delta dun1Delta strains exhibited irreversible hypersensitivity to HU and persistent activation of Rad53 [5].
 

Biological context of RAD53

 

Anatomical context of RAD53

  • Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain [11].
 

Associations of RAD53 with chemical compounds

 

Physical interactions of RAD53

  • Since the phosphorylated form of Rad9p appears capable of interacting stably with Rad53p in vivo, this phosphorylation response likely controls checkpoint signaling by Rad9p [9].
  • We sought to determine whether the mediator requirement could be circumvented by making fusion proteins between the Mec1 binding partner Ddc2p and Rad53p [13].
 

Enzymatic interactions of RAD53

 

Regulatory relationships of RAD53

 

Other interactions of RAD53

  • Analysis of viable null alleles revealed that Mec1 plays a greater role in response to inhibition of DNA synthesis than Rad53 [7].
  • Mutants defective for both pathways are severely deficient in Rad53p phosphorylation and RNR3 induction and are significantly more sensitive to DNA damage and replication blocks than single mutants alone [24].
  • On the basis of these observations, we suggest that the Rad53-dependent phosphorylation of Swi6 may delay the transition to S phase by inhibiting CLN transcription [8].
  • However, both chk1 and rad53 mutants are able to exit from mitosis and initiate a new cell cycle, suggesting that both pathways have supporting functions in restraining anaphase and in blocking the inactivation of mitotic cyclin-Cdk1 complexes [25].
  • RAD9 and RAD24 define two additive, interacting branches of the DNA damage checkpoint pathway in budding yeast normally required for Rad53 modification and activation [26].
 

Analytical, diagnostic and therapeutic context of RAD53

References

  1. Mdt1, a novel Rad53 FHA1 domain-interacting protein, modulates DNA damage tolerance and G(2)/M cell cycle progression in Saccharomyces cerevisiae. Pike, B.L., Yongkiettrakul, S., Tsai, M.D., Heierhorst, J. Mol. Cell. Biol. (2004) [Pubmed]
  2. A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Gunjan, A., Verreault, A. Cell (2003) [Pubmed]
  3. Interaction between Set1p and checkpoint protein Mec3p in DNA repair and telomere functions. Corda, Y., Schramke, V., Longhese, M.P., Smokvina, T., Paciotti, V., Brevet, V., Gilson, E., Géli, V. Nat. Genet. (1999) [Pubmed]
  4. The DNA replication checkpoint response stabilizes stalled replication forks. Lopes, M., Cotta-Ramusino, C., Pellicioli, A., Liberi, G., Plevani, P., Muzi-Falconi, M., Newlon, C.S., Foiani, M. Nature (2001) [Pubmed]
  5. Ccr4 contributes to tolerance of replication stress through control of CRT1 mRNA poly(A) tail length. Woolstencroft, R.N., Beilharz, T.H., Cook, M.A., Preiss, T., Durocher, D., Tyers, M. J. Cell. Sci. (2006) [Pubmed]
  6. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Sanchez, Y., Desany, B.A., Jones, W.J., Liu, Q., Wang, B., Elledge, S.J. Science (1996) [Pubmed]
  7. Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. Desany, B.A., Alcasabas, A.A., Bachant, J.B., Elledge, S.J. Genes Dev. (1998) [Pubmed]
  8. Rad53-dependent phosphorylation of Swi6 and down-regulation of CLN1 and CLN2 transcription occur in response to DNA damage in Saccharomyces cerevisiae. Sidorova, J.M., Breeden, L.L. Genes Dev. (1997) [Pubmed]
  9. MEC1-dependent phosphorylation of Rad9p in response to DNA damage. Emili, A. Mol. Cell (1998) [Pubmed]
  10. A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Zhao, X., Muller, E.G., Rothstein, R. Mol. Cell (1998) [Pubmed]
  11. SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the Cytoskeleton. Haque, F., Lloyd, D.J., Smallwood, D.T., Dent, C.L., Shanahan, C.M., Fry, A.M., Trembath, R.C., Shackleton, S. Mol. Cell. Biol. (2006) [Pubmed]
  12. Spk1/Rad53 is regulated by Mec1-dependent protein phosphorylation in DNA replication and damage checkpoint pathways. Sun, Z., Fay, D.S., Marini, F., Foiani, M., Stern, D.F. Genes Dev. (1996) [Pubmed]
  13. A Ddc2-Rad53 fusion protein can bypass the requirements for RAD9 and MRC1 in Rad53 activation. Lee, S.J., Duong, J.K., Stern, D.F. Mol. Biol. Cell (2004) [Pubmed]
  14. SPK1 is an essential S-phase-specific gene of Saccharomyces cerevisiae that encodes a nuclear serine/threonine/tyrosine kinase. Zheng, P., Fay, D.S., Burton, J., Xiao, H., Pinkham, J.L., Stern, D.F. Mol. Cell. Biol. (1993) [Pubmed]
  15. Rad53 phosphorylation site clusters are important for Rad53 regulation and signaling. Lee, S.J., Schwartz, M.F., Duong, J.K., Stern, D.F. Mol. Cell. Biol. (2003) [Pubmed]
  16. 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]
  17. Interferon-gamma activation of a mitogen-activated protein kinase, KFR1, in the bloodstream form of Trypanosoma brucei. Hua, S.B., Wang, C.C. J. Biol. Chem. (1997) [Pubmed]
  18. Rfc5, a replication factor C component, is required for regulation of Rad53 protein kinase in the yeast checkpoint pathway. Sugimoto, K., Ando, S., Shimomura, T., Matsumoto, K. Mol. Cell. Biol. (1997) [Pubmed]
  19. The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Allen, J.B., Zhou, Z., Siede, W., Friedberg, E.C., Elledge, S.J. Genes Dev. (1994) [Pubmed]
  20. Functional and physical interaction between Rad24 and Rfc5 in the yeast checkpoint pathways. Shimomura, T., Ando, S., Matsumoto, K., Sugimoto, K. Mol. Cell. Biol. (1998) [Pubmed]
  21. Mrc1 and Tof1 promote replication fork progression and recovery independently of Rad53. Tourrière, H., Versini, G., Cordón-Preciado, V., Alabert, C., Pasero, P. Mol. Cell (2005) [Pubmed]
  22. Pph3-Psy2 is a phosphatase complex required for Rad53 dephosphorylation and replication fork restart during recovery from DNA damage. O'Neill, B.M., Szyjka, S.J., Lis, E.T., Bailey, A.O., Yates, J.R., Aparicio, O.M., Romesberg, F.E. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  23. Reconstitution of Rad53 activation by Mec1 through adaptor protein Mrc1. Chen, S.H., Zhou, H. J. Biol. Chem. (2009) [Pubmed]
  24. 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]
  25. The DNA damage checkpoint and PKA pathways converge on APC substrates and Cdc20 to regulate mitotic progression. Searle, J.S., Schollaert, K.L., Wilkins, B.J., Sanchez, Y. Nat. Cell Biol. (2004) [Pubmed]
  26. 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]
  27. Involvement of the PP2C-like phosphatase Ptc2p in the DNA checkpoint pathways of Saccharomyces cerevisiae. Marsolier, M.C., Roussel, P., Leroy, C., Mann, C. Genetics (2000) [Pubmed]
  28. Regulation of DNA-replication origins during cell-cycle progression. Shirahige, K., Hori, Y., Shiraishi, K., Yamashita, M., Takahashi, K., Obuse, C., Tsurimoto, T., Yoshikawa, H. Nature (1998) [Pubmed]
  29. Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Cotta-Ramusino, C., Fachinetti, D., Lucca, C., Doksani, Y., Lopes, M., Sogo, J., Foiani, M. Mol. Cell (2005) [Pubmed]
 
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