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Molecular and Cellular Biology, March 2001, p. 1854-1865, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1854-1865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

Caitlin Hall,1 David M. Nelson,1 Xiaofen Ye,1 Kayla Baker,2 James A. DeCaprio,2 Steven Seeholzer,1 Marc Lipinski,3 and Peter D. Adams1,*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 191111; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 021152; and Institut Gustave Roussy, Villejuif, France3

Received 20 July 2000/Returned for modification 11 September 2000/Accepted 7 December 2000

Substrates of cyclin-cdk2 kinases contain two distinct primary sequence motifs: a cyclin-binding RXL motif and one or more phosphoacceptor sites (consensus S/TPXK/R or S/TP). To identify novel cyclin-cdk2 substrates, we searched the database for proteins containing both of these motifs. One such protein is human HIRA, the homologue of two cell cycle-regulated repressors of histone gene expression in Saccharomyces cerevisiae, Hir1p and Hir2p. Here we demonstrate that human HIRA is an in vivo substrate of a cyclin-cdk2 kinase. First, HIRA bound to and was phosphorylated by cyclin A- and E-cdk2 in vitro in an RXL-dependent manner. Second, HIRA was phosphorylated in vivo on two consensus cyclin-cdk2 phosphoacceptor sites and at least one of these, threonine 555, was phosphorylated by cyclin A-cdk2 in vitro. Third, phosphorylation of HIRA in vivo was blocked by cyclin-cdk2 inhibitor p21cip1. Fourth, HIRA became phosphorylated on threonine 555 in S phase when cyclin-cdk2 kinases are active. Fifth, HIRA was localized preferentially to the nucleus, where active cyclin A- and E-cdk2 are located. Finally, ectopic expression of HIRA in cells caused arrest in S phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-7108. Fax: (215) 728-3616. E-mail: pd_adams{at}fccc.edu.

Molecular and Cellular Biology, March 2001, p. 1854-1865, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1854-1865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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