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A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.

Eukaryotes have numerous checkpoint pathways to protect genome fidelity during normal cell division and in response to DNA damage. Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (for TopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that is required to prevent mitotic entry after treatment with ionizing radiation. Ticrr deficiency is embryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycle progression. Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint, leading to premature mitotic entry and mitotic catastrophe. We show that the human TICRR ortholog associates with TopBP1, a known checkpoint protein and a core component of the DNA replication preinitiation complex (pre-IC), and that the TICRR-TopBP1 interaction is stable without chromatin and requires BRCT motifs essential for TopBP1's replication and checkpoint functions. Most importantly, we find that ticrr deficiency disrupts chromatin binding of pre-IC, but not prereplication complex, components. Taken together, our data show that TICRR acts in association with TopBP1 and plays an essential role in pre-IC formation. It remains to be determined whether Ticrr represents the vertebrate ortholog of the yeast pre-IC component Sld3, or a hitherto unknown metazoan replication and checkpoint regulator.

Pubmed ID: 20080954

Authors

  • Sansam CL
  • Cruz NM
  • Danielian PS
  • Amsterdam A
  • Lau ML
  • Hopkins N
  • Lees JA

Journal

Genes & development

Publication Data

January 15, 2010

Associated Grants

None

Mesh Terms

  • Animals
  • Carrier Proteins
  • Chromatin
  • DNA Replication
  • DNA-Binding Proteins
  • Embryo, Nonmammalian
  • Genes, cdc
  • Humans
  • Mitosis
  • Mutation
  • Phenotype
  • Zebrafish
  • Zebrafish Proteins