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

Nature. 2003 Jun 19;423(6942):885-9. doi: 10.1038/nature01747.


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 complex. The removal of licensing proteins from chromatin during the S phase ensures that origins fire only once per cell cycle. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Cycle
  • DNA Replication*
  • DNA, Helminth / analysis
  • DNA, Helminth / biosynthesis
  • DNA, Helminth / genetics
  • Genome*
  • Ligases / genetics
  • Ligases / metabolism*
  • RNA Interference
  • RNA, Helminth / genetics
  • RNA, Helminth / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ubiquitin-Protein Ligases


  • Caenorhabditis elegans Proteins
  • Cdt-1 protein, C elegans
  • Cul-4 protein, C elegans
  • DNA, Helminth
  • RNA, Helminth
  • RNA, Messenger
  • Ubiquitin-Protein Ligases
  • Ligases