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DUN1  -  Dun1p

Saccharomyces cerevisiae S288c

Synonyms: D2370, DNA damage response protein kinase DUN1, YDL101C
 
 
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Disease relevance of DUN1

  • 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 [1].
 

High impact information on DUN1

  • Unlike sad1 mutants defective for multiple cell cycle checkpoints, pol2 mutants are defective only for the S phase checkpoint and the activation of DUN1 kinase necessary for the transcriptional response to damage [2].
  • DUN1 encodes a protein kinase that controls the DNA damage response in yeast [3].
  • Each is sensitive to DNA damage. dun1 mutants are also defective for RNR1 and RNR2 induction but are proficient for induction of other genes, defining the existence of at least two distinct DNA damage induction pathways [3].
  • Activation of Dun1 in response to replication blocks or DNA damage is blocked in sad1 mutants [4].
  • RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast [5].
 

Biological context of DUN1

  • We suggest that one function of DUN1-mediated DNA damage-induced gene expression is to channel the repair of UV damage into a nonrecombinogenic repair pathway [6].
  • We demonstrated that null alleles of DUN1 and certain mutant alleles of RFA2 result in short telomeres [7].
  • Radiosensitive and mitotic recombination phenotypes of the Saccharomyces cerevisiae dun1 mutant defective in DNA damage-inducible gene expression [6].
  • Spontaneous sister chromatid exchange (SCE), as monitored between truncated his3 fragments, was not enhanced in dun1 mutants, but UV-induced SCE and heteroallelic recombination were enhanced [6].
  • The yeast Dun1 kinase has complex checkpoint functions including DNA damage-dependent cell cycle arrest in G(2)/M, transcriptional induction of repair genes, and regulation of postreplicative DNA repair pathways [8].
 

Associations of DUN1 with chemical compounds

 

Enzymatic interactions of DUN1

  • In addition, Dun1p substrates with no SQ or TQ motifs are phosphorylated by Mec1p in vitro very inefficiently, but retain most of their ability to be phosphorylated by Tel1p [7].
  • Finally, Dun1 can phosphorylate Sml1 in vitro [11].
 

Regulatory relationships of DUN1

  • Interestingly, the expression of CRT10 itself is induced by DNA damaging agents and this induction requires DUN1, suggesting that CRT10 plays a role in cellular response to DNA damage and replication blocks [9].
 

Other interactions of DUN1

  • The dun1 and rad52 single mutants were similar in terms of UV sensitivities; however, the dun1 rad52 double mutant exhibited a synergistic decrease in UV resistance [6].
  • We suggest that a form of Dun1 may be a negative regulator of the DIN7 gene expression [12].
  • We also showed that Rfa2p (a subunit of RPA) and the Dun1p checkpoint kinase, which are required for DNA damage repair and which are phosphorylated in response to DNA damage in vivo, are in vitro substrates of the Tel1p and Mec1p kinases [7].
  • Moreover, inducible overexpression of RAD5 mimicked the double mutant phenotype by hypersensitizing dun1 mutants to replication blocks [8].
  • Downstream checkpoint kinases Chk1 and Dun1 play no detectable role in either promoting degradation or inhibiting it [13].
 

Analytical, diagnostic and therapeutic context of DUN1

  • Quantitative mutagenicity assay and Northern blot analysis demonstrated dependence of induction of Ty1 element by DNA-damaging agents on the function of RAD9 gene and independence on DUN1 gene [14].
  • Crystallization and preliminary X-ray diffraction studies of FHA domains of Dun1 and Rad53 protein kinases [15].

References

  1. 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]
  2. DNA polymerase epsilon links the DNA replication machinery to the S phase checkpoint. Navas, T.A., Zhou, Z., Elledge, S.J. Cell (1995) [Pubmed]
  3. DUN1 encodes a protein kinase that controls the DNA damage response in yeast. Zhou, Z., Elledge, S.J. Cell (1993) [Pubmed]
  4. 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]
  5. RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast. Gardner, R., Putnam, C.W., Weinert, T. EMBO J. (1999) [Pubmed]
  6. Radiosensitive and mitotic recombination phenotypes of the Saccharomyces cerevisiae dun1 mutant defective in DNA damage-inducible gene expression. Fasullo, M., Koudelik, J., AhChing, P., Giallanza, P., Cera, C. Genetics (1999) [Pubmed]
  7. Amino acid changes in Xrs2p, Dun1p, and Rfa2p that remove the preferred targets of the ATM family of protein kinases do not affect DNA repair or telomere length in Saccharomyces cerevisiae. Mallory, J.C., Bashkirov, V.I., Trujillo, K.M., Solinger, J.A., Dominska, M., Sung, P., Heyer, W.D., Petes, T.D. DNA Repair (Amst.) (2003) [Pubmed]
  8. Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. Hammet, A., Pike, B.L., Heierhorst, J. J. Biol. Chem. (2002) [Pubmed]
  9. Identification and characterization of CRT10 as a novel regulator of Saccharomyces cerevisiae ribonucleotide reductase genes. Fu, Y., Xiao, W. Nucleic Acids Res. (2006) [Pubmed]
  10. Role of the casein kinase I isoform, Hrr25, and the cell cycle-regulatory transcription factor, SBF, in the transcriptional response to DNA damage in Saccharomyces cerevisiae. Ho, Y., Mason, S., Kobayashi, R., Hoekstra, M., Andrews, B. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  11. The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Zhao, X., Rothstein, R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  12. Characterization of a novel DNA damage-inducible gene of Saccharomyces cerevisiae, DIN7, which is a structural homolog of the RAD2 and RAD27 DNA repair genes. Mieczkowski, P.A., Fikus, M.U., Ciesla, Z. Mol. Gen. Genet. (1997) [Pubmed]
  13. 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]
  14. Activation of Ty transposition by mutagens. Staleva Staleva, L., Venkov, P. Mutat. Res. (2001) [Pubmed]
  15. Crystallization and preliminary X-ray diffraction studies of FHA domains of Dun1 and Rad53 protein kinases. Blanchard , H., Fontes , M.R., Hammet , A., Pike , B.L., Teh , T., Gleichmann , T., Gooley , P.R., Kobe , B., Heierhorst , J. Acta Crystallogr. D Biol. Crystallogr. (2001) [Pubmed]
 
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