CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing

Weiwei Zhong, Hui Feng, Fernando E. Santiago and Edward T. Kipreos ()
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Weiwei Zhong: University of Georgia
Hui Feng: University of Georgia
Fernando E. Santiago: University of Georgia
Edward T. Kipreos: University of Georgia

Nature, 2003, vol. 423, issue 6942, 885-889

Abstract: Abstract To maintain genome stability, DNA replication is strictly regulated to occur only once per cell cycle. In eukaryotes, the presence of ‘licensing proteins’ at replication origins during the G1 cell-cycle phase allows the formation of the pre-replicative complex1. The removal of licensing proteins from chromatin during the S phase ensures that origins fire only once per cell cycle1. Here we show that the CUL-4 ubiquitin ligase temporally restricts DNA-replication licensing in Caenorhabditis elegans. Inactivation of CUL-4 causes massive DNA re-replication, producing cells with up to 100C DNA content. The C. elegans orthologue of the replication-licensing factor Cdt1 (refs 2, 3) is required for DNA replication. C. elegans CDT-1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL-4, CDT-1 levels fail to decrease during S phase and instead remain constant in the re-replicating cells. Removal of one genomic copy of cdt-1 suppresses the cul-4 re-replication phenotype. We propose that CUL-4 prevents aberrant re-initiation of DNA replication, at least in part, by facilitating the degradation of CDT-1.

Date: 2003
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DOI: 10.1038/nature01747

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