A p53-dependent checkpoint pathway prevents rereplication |
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Authors: | Vaziri Cyrus Saxena Sandeep Jeon Yesu Lee Charles Murata Kazutaka Machida Yuichi Wagle Nikhil Hwang Deog Su Dutta Anindya |
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Affiliation: | Cancer Center, Department of Medicine, Boston University School of Medicine, 80 East Concord Street, Massachusetts 02118, USA. |
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Abstract: | Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability. |
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