Histone H3 lysine 36 methyltransferase mobilizes NER factors to regulate tolerance against alkylation damage in fission yeast

Nucleic Acids Res. 2018 Jun 1;46(10):5061-5074. doi: 10.1093/nar/gky245.


The Set2 methyltransferase and its target, histone H3 lysine 36 (H3K36), affect chromatin architecture during the transcription and repair of DNA double-stranded breaks. Set2 also confers resistance against the alkylating agent, methyl methanesulfonate (MMS), through an unknown mechanism. Here, we show that Schizosaccharomyces pombe (S. pombe) exhibit MMS hypersensitivity when expressing a set2 mutant lacking the catalytic histone methyltransferase domain or a H3K36R mutant (reminiscent of a set2-null mutant). Set2 acts synergistically with base excision repair factors but epistatically with nucleotide excision repair (NER) factors, and determines the timely nuclear accumulation of the NER initiator, Rhp23, in response to MMS. Set2 facilitates Rhp23 recruitment to chromatin at the brc1 locus, presumably to repair alkylating damage and regulate the expression of brc1+ in response to MMS. Set2 also show epistasis with DNA damage checkpoint proteins; regulates the activation of Chk1, a DNA damage response effector kinase; and acts in a similar functional group as proteins involved in homologous recombination. Consistently, Set2 and H3K36 ensure the dynamicity of Rhp54 in DNA repair foci formation after MMS treatment. Overall, our results indicate a novel role for Set2/H3K36me in coordinating the recruitment of DNA repair machineries to timely manage alkylating damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology*
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair / drug effects
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epistasis, Genetic
  • Gene Expression Regulation, Fungal
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Lysine / metabolism
  • Methyl Methanesulfonate / pharmacology
  • Methylation / drug effects
  • Protein Domains
  • Schizosaccharomyces / drug effects*
  • Schizosaccharomyces / genetics*
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*


  • Alkylating Agents
  • DNA-Binding Proteins
  • RHP23 protein, S pombe
  • Schizosaccharomyces pombe Proteins
  • Methyl Methanesulfonate
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, S pombe
  • Checkpoint Kinase 1
  • Chk1 protein, S pombe
  • DNA Helicases
  • Rhp54 protein, S pombe
  • Lysine