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J. Biol. Chem., Vol. 282, Issue 12, 8793-8800, March 23, 2007

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Rad4^TopBP1 Associates with Srr2, an Spc1 MAPK-regulated Protein, in Response to Environmental Stress^*

From the Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324

Rad4^TopBP1 is a scaffold in a protein complex containing both replication proteins and checkpoint proteins and plays essential roles in both replication and checkpoint responses. We have previously identified four novel fission yeast mutants of rad4^+TopBP1 to explore how Rad4^TopBP1, a single protein, can play multiple roles in genomic integrity maintenance. Among the four novel mutants, rad4-c17^TopBP1 is a thermosensitive mutant. Here, we characterized rad4-c17^TopBP1 and identified a rad4-c17^TopBP1 allele specific suppressor named srr2⁺ (suppressor of Rad4^TopBP1 R2 domain). srr2⁺ has previously been identified as an environmental stress-responsive gene (GenBank^TM accession number AL049644 [GenBank] .1, locus spcc191.01). srr2⁺ null cells are sensitive to hydroxyurea (HU) at elevated temperatures. Deletion of srr2⁺ in rad4-c17^TopBP1 exacerbates the HU sensitivity of the mutant. Overexpression of srr2⁺ suppresses the rad4-c17^TopBP1 mutant sensitivity to temperature and HU and restores the compromised ability of rad4-c17^TopBP1 to activating Cds1 kinase in response to HU treatment. Furthermore, stress-activated MAPK, Spc1 (also known as StyI or Phh1), induces the expression and phosphorylation of the Srr2 protein. Significantly, environmental stress induces co-precipitation of Srr2 protein with Rad4^TopBP1, and the co-precipitation is compromised in the rad4-c17^TopBP1 mutant. These results have led us to propose a model; Rad4^TopBP1 exists in a large protein complex to coordinate genomic perturbations with checkpoint responses to maintain genomic integrity. In addition, when cells experience environmental stress, Rad4^TopBP1 associates with Srr2, an Spc1 MAPK-responsive protein, to survive the stress, potentially by providing a link of the Spc1 MAPK response to checkpoint responses.

Received for publication, October 2, 2006 , and in revised form, February 1, 2007.

^* This work is supported by NCI, National Institutes of Health Grant CA54415. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 650-725-4907; Fax: 650-725-4905; E-mail: tswang{at}stanford.edu.

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