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Gene Review

SML1  -  Sml1p

Saccharomyces cerevisiae S288c

Synonyms: Ribonucleotide reductase inhibitor protein SML1, YM9958.04, YML058W
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High impact information on SML1

  • Finally, both in vivo and in vitro experiments show that Sml1 binds to Rnr1 [1].
  • Their essential role in growth can be bypassed by deletion of a novel gene, SML1, which functions after several genes whose overexpression also suppresses mec1 inviability [1].
  • More over, failure to remove Sml1 in mec1 and rad53 mutants results in incomplete DNA replication, defective mitochondrial DNA propagation, decreased dNTP levels and cell death [2].
  • Interestingly, similar regulation of Sml1 also occurs after DNA damage [2].
  • The disappearance of Sml1 protein in S phase is due to post-transcriptional regulation and is associated with protein phosphorylation [2].

Biological context of SML1

  • To understand further the relationship between this suppression and the Sml1-Rnr1 interaction, we randomly mutagenized the SML1 open reading frame [3].
  • Here we show that their role in growth is to remove the ribonucleotide reductase inhibitor Sml1 to ensure DNA replication [2].
  • Sedimentation equilibrium measurements in the analytical ultracentrifuge show that both wild-type and C14S Sml1p exist as dimers in solution, indicating that the dimerization is not a result of a disulfide bond [4].
  • In contrast, the enhanced sensitivity of doa4-10 mutant cells to Top1T722Ap was unrelated to alterations in endocytosis and was selectively suppressed by increased dosage of the ribonucleotide reductase inhibitor Sml1p [5].

Associations of SML1 with chemical compounds

  • Deletion of CRT10 resulted in an enhanced resistance to HU reminiscent of the inactivation of two other ribonucleotide reductase (Rnr) suppressors, CRT1 and SML1, which regulate Rnr activity at transcriptional and translational levels, respectively [6].
  • To determine whether disulfide bonding is essential for Sml1p oligomerization, we mutated the Cys14 to serine [4].
  • Mass spectrometric analysis of wild-type Sml1p revealed an intermolecular disulfide bond involving the cysteine residue at position 14 of the primary sequence [4].
  • By using high-performance mass spectrometry to characterize the oxidized peptides created by the hydroxyl radical reactions, amino acid solvent-accessibility data for native and denatured C14S Sml1p that revealed a solvent-excluding tertiary structure in the native state were obtained [7].
  • Sml1p is small protein that binds to and inhibits the activity of ribonucleotide reductase (RNR)3, a protein enzyme complex that controls the balance and level of the cellular deoxynucleotide diphosphate pools that are critical for DNA synthesis and repair [8].

Enzymatic interactions of SML1


Regulatory relationships of SML1

  • We found that the ubiquitin protein ligase activity of Not4p does not play a role in HU induced Sml1p degradation [10].

Other interactions of SML1

  • In addition, sml1 affects various cellular processes analogous to overproducing the large subunit of ribonucleotide reductase, RNR1 [1].
  • In addition, deletion of RRM3 or SML1 fully rescued the approximately 50% depletion of mtDNA observed in a pif1 null strain [11].
  • The absence of Dun1 activity leads to the accumulation of Sml1 protein at S phase and after DNA damage [9].

Analytical, diagnostic and therapeutic context of SML1


  1. 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]
  2. The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage. Zhao, X., Chabes, A., Domkin, V., Thelander, L., Rothstein, R. EMBO J. (2001) [Pubmed]
  3. Mutational and structural analyses of the ribonucleotide reductase inhibitor Sml1 define its Rnr1 interaction domain whose inactivation allows suppression of mec1 and rad53 lethality. Zhao, X., Georgieva, B., Chabes, A., Domkin, V., Ippel, J.H., Schleucher, J., Wijmenga, S., Thelander, L., Rothstein, R. Mol. Cell. Biol. (2000) [Pubmed]
  4. Sml1p is a dimer in solution: characterization of denaturation and renaturation of recombinant Sml1p. Gupta, V., Peterson, C.B., Dice, L.T., Uchiki, T., Racca, J., Guo, J.T., Xu, Y., Hettich, R., Zhao, X., Rothstein, R., Dealwis, C.G. Biochemistry (2004) [Pubmed]
  5. The deubiquitinating enzyme Doa4p protects cells from DNA topoisomerase I poisons. Fiorani, P., Reid, R.J., Schepis, A., Jacquiau, H.R., Guo, H., Thimmaiah, P., Benedetti, P., Bjornsti, M.A. J. Biol. Chem. (2004) [Pubmed]
  6. Identification and characterization of CRT10 as a novel regulator of Saccharomyces cerevisiae ribonucleotide reductase genes. Fu, Y., Xiao, W. Nucleic Acids Res. (2006) [Pubmed]
  7. Photochemical surface mapping of C14S-Sml1p for constrained computational modeling of protein structure. Sharp, J.S., Guo, J.T., Uchiki, T., Xu, Y., Dealwis, C., Hettich, R.L. Anal. Biochem. (2005) [Pubmed]
  8. Characterization of monomeric and dimeric forms of recombinant Sml1p-histag protein by electrospray mass spectrometry. Uchiki, T., Hettich, R., Gupta, V., Dealwis, C. Anal. Biochem. (2002) [Pubmed]
  9. 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]
  10. DNA damage and replication stress induced transcription of RNR genes is dependent on the Ccr4-Not complex. Mulder, K.W., Winkler, G.S., Timmers, H.T. Nucleic Acids Res. (2005) [Pubmed]
  11. The conserved Mec1/Rad53 nuclear checkpoint pathway regulates mitochondrial DNA copy number in Saccharomyces cerevisiae. Taylor, S.D., Zhang, H., Eaton, J.S., Rodeheffer, M.S., Lebedeva, M.A., O'rourke, T.W., Siede, W., Shadel, G.S. Mol. Biol. Cell (2005) [Pubmed]
  12. Identification of phosphorylation sites on the yeast ribonucleotide reductase inhibitor Sml1. Uchiki, T., Dice, L.T., Hettich, R.L., Dealwis, C. J. Biol. Chem. (2004) [Pubmed]
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