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MBC in Press, published online ahead of print January 10, 2007
Mol. Biol. Cell 10.1091/mbc.E06-10-0957

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Submitted on October 27, 2006
Revised on December 21, 2006
Accepted on December 29, 2006

Increased Common Fragile Site Expression, Cell Proliferation Defects, and Apoptosis following Conditional Inactivation of Mouse Hus1 in Primary Cultured Cells

Min Zhu and Robert S. Weiss

Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853

Monitoring Editor: Orna Cohen-Fix

Targeted disruption of the mouse Hus1 cell cycle checkpoint gene results in embryonic lethality and proliferative arrest in cultured cells. To investigate the essential functions of Hus1, we developed a system for the regulated inactivation of mouse Hus1 in primary fibroblasts. Inactivation of a loxP site-flanked conditional Hus1 allele using a cre-expressing adenovirus resulted in reduced cell doubling, cell cycle alterations, and increased apoptosis. These phenotypes were associated with a significantly increased frequency of gross chromosomal abnormalities and an S-phase specific accumulation of phosphorylated histone H2AX, an indicator of double-stranded DNA breaks. To determine whether these chromosomal abnormalities occurred randomly or at specific genomic regions, we assessed the stability of common fragile sites, chromosomal loci that are prone to breakage in cells undergoing replication stress. Hus1 was found to be essential for fragile site stability, as spontaneous chromosomal abnormalities occurred preferentially at common fragile sites upon conditional Hus1 inactivation. Although p53 levels increased following Hus1 loss, deletion of p53 failed to rescue the cell doubling defect or increased apoptosis in conditional Hus1 knockout cells. In summary, we propose that Hus1 loss leads to chromosomal instability during DNA replication, triggering increased apoptosis and impaired proliferation through p53-independent mechanisms.

Address correspondence to: Robert S. Weiss (rsw26{at}cornell.edu)




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