ZFIN ID: ZDB-PUB-100119-22
A vertebrate gene, ticrr, is an essential checkpoint and replication regulator
Sansam, C.L., Cruz, N.M., Danielian, P.S., Amsterdam, A., Lau, M.L., Hopkins, N., and Lees, J.A.
Date: 2010
Source: Genes & Development   24(2): 183-194 (Journal)
Registered Authors: Amsterdam, Adam, Hopkins, Nancy, Sansam, Chris
Keywords: DNA replication, S/M checkpoint, G2/M checkpoint, pre-RC, pre-IC, TopBP1, SLD3
MeSH Terms:
  • Animals
  • Carrier Proteins/genetics*
  • Carrier Proteins/metabolism*
  • Chromatin/metabolism
  • DNA Replication/genetics*
  • DNA-Binding Proteins/metabolism
  • Embryo, Nonmammalian
  • Genes, cdc/physiology*
  • Humans
  • Mitosis/genetics*
  • Mutation/genetics
  • Phenotype
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
PubMed: 20080954 Full text @ Genes & Dev.
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.