Journal
SCIENCE
Volume 340, Issue 6135, Pages 981-984Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1237448
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Funding
- Cancer Research UK
- European Research Council [249883-EUKDNAREP]
- Association for International Cancer Research grant [10-0270]
- European Molecular Biology Organization Long Term Fellowship
- Cancer Research UK [15669] Funding Source: researchfish
- Worldwide Cancer Research [10-0270] Funding Source: researchfish
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Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holoheticase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.
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