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Identification of a Heteromeric Complex That Promotes DNA Replication Origin Firing in Human Cells

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Science  24 May 2013:
Vol. 340, Issue 6135, pp. 981-984
DOI: 10.1126/science.1237448

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Keeping Coordinated

Before a cell divides, it must replicate its genome so that both daughter cells receive a copy of the parental DNA. Replication must be tightly regulated to ensure that the genome is replicated only once, because over- or underreplication could result in aberrations that cause genome instability. Thus, replication must be coordinated with other events in the cell, such as the cell cycle and DNA damage response systems. Boos et al. (p. 981) analyzed the function of the Treslin/TICRR protein, an essential DNA replication factor regulated by cyclin-dependent kinases and the DNA damage checkpoint. Treslin interacts with the Mdm Two Binding Protein (MTBP), implicated in oncogenesis. MTBP and Treslin appear to integrate signals from the cell cycle and the DNA damage–response pathway, thereby controlling the initiation of DNA replication.

Abstract

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) holohelicase 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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