Hug1 is an intrinsically disordered protein that inhibits ribonucleotide reductase activity by directly binding Rnr2 subunit

Nucleic Acids Res. 2014 Dec 1;42(21):13174-85. doi: 10.1093/nar/gku1095. Epub 2014 Nov 6.


Rad53 is a conserved protein kinase with a central role in DNA damage response and nucleotide metabolism. We observed that the expression of a dominant-lethal form of RAD53 leads to significant expression changes for at least 16 genes, including the RNR3 and the HUG1 genes, both of which are involved in the control of nucleotide metabolism. We established by multiple biophysical and biochemical approaches that Hug1 is an intrinsically disordered protein that directly binds to the small RNR subunit Rnr2. We characterized the surface of interaction involved in Hug1 binding to Rnr2, and we thus defined a new binding region to Rnr2. Moreover, we show that Hug1 is deleterious to cell growth in the context of reduced RNR activity. This inhibitory effect of Hug1 on RNR activity depends on the binding of Hug1 to Rnr2. We propose a model in which Hug1 modulates Rnr2-Rnr1 association by binding Rnr2. We show that Hug1 accumulates under various physiological conditions of high RNR induction. Hence, both the regulation and the mode of action of Hug1 are different from those of the small protein inhibitors Dif1 and Sml1, and Hug1 can be considered as a regulator for fine-tuning of RNR activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / enzymology
  • Checkpoint Kinase 2 / metabolism
  • DNA Damage
  • DNA Replication
  • Gene Deletion
  • Gene Expression Regulation, Fungal
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / metabolism*
  • Mutation
  • Protein Binding
  • Protein Structure, Secondary
  • Ribonucleotide Reductases / analysis
  • Ribonucleotide Reductases / antagonists & inhibitors
  • Ribonucleotide Reductases / genetics
  • Ribonucleotide Reductases / metabolism*
  • Saccharomyces cerevisiae Proteins / analysis
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / biosynthesis
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Cell Cycle Proteins
  • Dif1 protein, S cerevisiae
  • HUG1 protein, S cerevisiae
  • Intrinsically Disordered Proteins
  • Saccharomyces cerevisiae Proteins
  • RNR2 protein, S cerevisiae
  • Ribonucleotide Reductases
  • Checkpoint Kinase 2
  • RAD53 protein, S cerevisiae