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Rad4TopBP1 associates with Srr2, an Spc1 MAPK-regulated protein, in response to environmental stress

Lorena Taricani1, Teresa S F Wang

  • 1Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA.

The Journal of Biological Chemistry
|February 3, 2007
PubMed

Insights

Rad4(TopBP1) protein maintains genomic integrity through complex interactions. A novel suppressor, Srr2, links environmental stress responses to Rad4(TopBP1) checkpoint functions.

Area of Science:

  • * Molecular Biology
  • * Genetics
  • * Cellular Biology

Background:

  • * Rad4(TopBP1) is a crucial scaffold protein involved in DNA replication and checkpoint control, essential for maintaining genomic integrity.
  • * Previous studies identified four fission yeast mutants of rad4+(TopBP1) to understand its multifaceted roles.
  • * The rad4-c17(TopBP1) mutant exhibits thermosensitivity, indicating a specific defect in Rad4(TopBP1) function.

Purpose of the Study:

  • * To characterize the novel thermosensitive mutant rad4-c17(TopBP1) in fission yeast.
  • * To identify and characterize a specific suppressor gene, srr2+, for the rad4-c17(TopBP1) mutant.
  • * To elucidate the functional relationship between Rad4(TopBP1), Srr2, and stress response pathways.

Main Methods:

  • * Genetic analysis of fission yeast mutants, including thermosensitive and null mutants.
  • * Hydroxyurea (HU) sensitivity assays at elevated temperatures.
  • * Analysis of Cds1 kinase activation in response to HU treatment.
  • * Investigation of Spc1 (stress-activated MAPK) pathway effects on Srr2.
  • * Co-immunoprecipitation assays to study protein-protein interactions under environmental stress.

Main Results:

  • * Identification of srr2+ as a specific suppressor of the rad4-c17(TopBP1) mutant phenotype.
  • * srr2+ null mutants display sensitivity to hydroxyurea (HU) at higher temperatures, and this sensitivity is exacerbated in the rad4-c17(TopBP1) srr2+ double mutant.
  • * Overexpression of srr2+ rescues the temperature and HU sensitivity of rad4-c17(TopBP1) and restores Cds1 kinase activation.
  • * The stress-activated MAPK Spc1 induces Srr2 expression and phosphorylation.
  • * Environmental stress promotes the association of Srr2 with Rad4(TopBP1), an interaction impaired in the rad4-c17(TopBP1) mutant.

Conclusions:

  • * Rad4(TopBP1) functions within a large complex to coordinate DNA damage responses and maintain genomic integrity.
  • * Srr2, a stress-responsive protein, associates with Rad4(TopBP1) under environmental stress conditions.
  • * The Rad4(TopBP1)-Srr2 interaction, potentially mediated by the Spc1 MAPK pathway, is crucial for cellular survival during stress and links environmental stress signaling to DNA checkpoint responses.

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