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Molecular and Cellular Biology, February 2003, p. 791-803, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.791-803.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Role for Mouse Hus1 in an S-Phase DNA Damage Cell Cycle Checkpoint

Robert S. Weiss,1,{dagger} Philip Leder,1,2* and Cyrus Vaziri3

Department of Genetics,1 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115,2 Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 021183

Received 15 August 2002/ Returned for modification 30 September 2002/ Accepted 1 November 2002

Mouse Hus1 encodes an evolutionarily conserved DNA damage response protein. In this study we examined how targeted deletion of Hus1 affects cell cycle checkpoint responses to genotoxic stress. Unlike hus1- fission yeast (Schizosaccharomyces pombe) cells, which are defective for the G2/M DNA damage checkpoint, Hus1-null mouse cells did not inappropriately enter mitosis following genotoxin treatment. However, Hus1-deficient cells displayed a striking S-phase DNA damage checkpoint defect. Whereas wild-type cells transiently repressed DNA replication in response to benzo(a)pyrene dihydrodiol epoxide (BPDE), a genotoxin that causes bulky DNA adducts, Hus1-null cells maintained relatively high levels of DNA synthesis following treatment with this agent. However, when treated with DNA strand break-inducing agents such as ionizing radiation (IR), Hus1-deficient cells showed intact S-phase checkpoint responses. Conversely, checkpoint-mediated inhibition of DNA synthesis in response to BPDE did not require NBS1, a component of the IR-responsive S-phase checkpoint pathway. Taken together, these results demonstrate that Hus1 is required specifically for one of two separable mammalian checkpoint pathways that respond to distinct forms of genome damage during S phase.

* Corresponding author. Mailing address for Cyrus Vaziri: Cancer Research Center, Boston University School of Medicine, 80 E. Concord St., Boston, MA 02118. Phone: (617) 638-4175. Fax: (617) 638-5609. E-mail: cvaziri{at}bu.edu Mailing address for Philip Leder: Department of Genetics, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 432-7667. Fax: (617) 432-7663. E-mail: leder{at}rascal.med.harvard.edu.

{dagger} Present address: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.

Molecular and Cellular Biology, February 2003, p. 791-803, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.791-803.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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