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Molecular and Cellular Biology, August 1999, p. 5535-5547, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Fission Yeast Gene, him1+/dfp1+, Encoding a Regulatory Subunit for Hsk1 Kinase, Plays Essential Roles in S-Phase Initiation as Well as in S-Phase Checkpoint Control and Recovery from DNA Damage

Tadayuki Takeda,1,2 Keiko Ogino,1,2 Etsuko Matsui,1,2 Min Kwan Cho,1 Hiroyuki Kumagai,1 Tsuyoshi Miyake,1,dagger Ken-ichi Arai,1,2 and Hisao Masai1,2,*

Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, 1 and CREST, Japan Science and Technology Corporation (JST),2 Tokyo 108-8639, Japan

Received 16 February 1999/Returned for modification 8 April 1999/Accepted 19 May 1999

Saccharomyces cerevisiae CDC7 encodes a serine/threonine kinase required for G1/S transition, and its related kinases are present in fission yeast as well as in higher eukaryotes, including humans. Kinase activity of Cdc7 protein depends on the regulatory subunit, Dbf4, which also interacts with replication origins. We have identified him1+ from two-hybrid screening with Hsk1, a fission yeast homologue of Cdc7 kinase, and showed that it encodes a regulatory subunit of Hsk1. Him1, identical to Dfp1, previously identified as an associated molecule of Hsk1, binds to Hsk1 and stimulates its kinase activity, which phosphorylates both catalytic and regulatory subunits as well as recombinant MCM2 protein in vitro. him1+ is essential for DNA replication in fission yeast cells, and its transcription is cell cycle regulated, increasing at middle M to late G1. The protein level is low at START in G1, increases at the G1/S boundary, and is maintained at a high level throughout S phase. Him1 protein is hyperphosphorylated at G1/S through S during the cell cycle as well as in response to early S-phase arrest induced by nucleotide deprivation. Deletion of one of the motifs conserved in regulatory subunits for Cdc7-related kinases as well as alanine substitution of three serine and threonine residues present in the same motif resulted in a defect in checkpoint regulation normally induced by hydroxyurea treatment. The alanine mutant also showed growth retardation after UV irradiation and the addition of methylmethane sulfonate. In keeping with this result, a database search indicates that him1+ is identical to rad35+. Our results reveal a novel function of the Cdc7/Dbf4-related kinase complex in S-phase checkpoint control as well as in growth recovery from DNA damage in addition to its predicted essential function in S-phase initiation.

* Corresponding author. Mailing address: Department of Molecular & Developmental Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5661. Fax: 81-3-5449-5424. E-mail: hisao{at}ims.u-tokyo.ac.jp.

dagger Present address: Department of Biochemistry Health Sciences Center, University of Virginia, Charlottesville, VA 22908.

Molecular and Cellular Biology, August 1999, p. 5535-5547, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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