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.
Sansam
Christopher L
CL
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cruz
Nelly M
NM
Danielian
Paul S
PS
Amsterdam
Adam
A
Lau
Melissa L
ML
Hopkins
Nancy
N
Lees
Jacqueline A
JA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D029961:Zebrafish Proteins