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Molecular and Cellular Biology, February 2003, p. 1441-1452, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1441-1452.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Direct Kinase-to-Kinase Signaling Mediated by the FHA Phosphoprotein Recognition Domain of the Dun1 DNA Damage Checkpoint Kinase

Vladimir I. Bashkirov,{dagger} Elena V. Bashkirova,{ddagger} Edwin Haghnazari, and Wolf-Dietrich Heyer*

Sections of Microbiology and of Molecular and Cellular Biology and Center for Genetics and Development, Division of Biological Sciences, University of California, Davis, Davis, California 95616-8665

Received 25 September 2002/ Accepted 31 October 2002

The serine-threonine kinase Dun1 contains a forkhead-associated (FHA) domain and functions in the DNA damage checkpoint pathway of Saccharomyces cerevisiae. It belongs to the Chk2 family of checkpoint kinases, which includes S. cerevisiae Rad53 and Mek1, Schizosaccharomyces pombe Cds1, and human Chk2. Dun1 is required for DNA damage-induced transcription of certain target genes, transient G2/M arrest after DNA damage, and DNA damage-induced phosphorylation of the DNA repair protein Rad55. Here we report that the FHA phosphoprotein recognition domain of Dun1 is required for direct phosphorylation of Dun1 by Rad53 kinase in vitro and in vivo. trans phosphorylation by Rad53 does not require the Dun1 kinase activity and is likely to involve only a transient interaction between the two kinases. The checkpoint functions of Dun1 kinase in DNA damage-induced transcription, G2/M cell cycle arrest, and Rad55 phosphorylation are severely compromised in an FHA domain mutant of Dun1. As a consequence, the Dun1 FHA domain mutant displays enhanced sensitivity to genotoxic stress induced by UV, methyl methanesulfonate, and the replication inhibitor hydroxyurea. We show that the Dun1 FHA domain is critical for direct kinase-to-kinase signaling from Rad53 to Dun1 in the DNA damage checkpoint pathway.

* Corresponding author. Mailing address: Section of Microbiology, University of California, Davis, Davis, CA 95616-8665. Phone: (530) 752-3001. Fax: (530) 752-3011. E-mail: wdheyer{at}ucdavis.edu.

{dagger} Permanent address: Institute of Gene Biology, Russian Academy of Sciences, Moscow 117334, Russia.

{ddagger} Present address: Novozymes, Inc., Davis, CA 95616.

Molecular and Cellular Biology, February 2003, p. 1441-1452, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1441-1452.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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