Slt2 (Mpk1) MAP kinase is involved in the response of Saccharomyces cerevisiae to 8-methoxypsoralen plus UVA

J Photochem Photobiol B. 2009 Jun 3;95(3):148-55. doi: 10.1016/j.jphotobiol.2009.02.001. Epub 2009 Feb 20.

Abstract

The bifunctional furocoumarin 8-methoxypsoralen (8-MOP) is a well established drug in the photochemotherapy of psoriasis and other skin diseases. In eukaryotic cells, this compound intercalates into DNA and undergoes photocycloaddition with pyrimidines to form monoadducts and interstrand crosslinks initiating a cascade of events leading to cytotoxic, mutagenic and carcinogenic responses. In yeast cells, exposure to 8-MOP plus UVA induces transcription of a large set of genes, and cellular reaction is different from an overall DNA damage response and specific to 8-MOP/UVA [M. Dardalhon, W. Lin, A. Nicolas, D. Averbeck, Specific transcriptional responses induced by 8-methoxypsoralen and UVA in yeast, FEMS Yeast Res. 7 (2007) 866-878]. To further define the relationship between induced genes and genotoxic consequences after 8-MOP/UVA treatment, the survival responses of mutants deleted for genes that are specifically induced by 8-MOP plus UVA were analysed in terms of survival. Six mutants deleted for RAD51, RAD54, DUN1, DIN7, already known to be implicated in DNA damage responses, and for SLT2/MPK1 and PDE2 involved in cell wall stress responses, were found sensitive to 8-MOP plus UVA treatment. Further characterization of slt2 mutant provides evidence for the existence of an 8-MOP/UVA response in yeast in which the yeast Slt2 MAPK pathway is implicated. Activation by 8-MOP plus UVA of this MAP kinase previously observed at the transcriptional level is now confirmed at the protein level. In addition to sensitivity to 8-MOP/UVA, yeast cells lacking SLT2 show reduced survival after 3-carbethoxypsoralen plus UVA and 1,6-dioxapyrene plus UVA. Osmotic support could suppress the sensitivities to these genotoxic agents, suggesting that these sensitivities are related to cell integrity defects and/or cell wall defects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Survival
  • DNA Damage
  • Furocoumarins / pharmacology
  • Furocoumarins / toxicity
  • Gene Deletion
  • Methoxsalen / pharmacology
  • Methoxsalen / toxicity*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Photosensitizing Agents / pharmacology
  • Photosensitizing Agents / toxicity*
  • Pyrenes / pharmacology
  • Pyrenes / toxicity
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / radiation effects*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Ultraviolet Rays*

Substances

  • Furocoumarins
  • Photosensitizing Agents
  • Pyrenes
  • Saccharomyces cerevisiae Proteins
  • 1,6-dioxapyrene
  • 3-carbethoxypsoralen
  • Mitogen-Activated Protein Kinases
  • SLT2 protein, S cerevisiae
  • Methoxsalen