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Science. 2013 May 24;340(6135):981-4. doi: 10.1126/science.1237448.

Identification of a heteromeric complex that promotes DNA replication origin firing in human cells.

Author information

1
Cancer Research UK London Research Institute (LRI), Clare Hall Laboratories, South Mimms, Herts., UK.

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.

PMID:
23704573
DOI:
10.1126/science.1237448
[Indexed for MEDLINE]

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