title: Identification of a heteromeric complex that promotes DNA replication origin firing in human cells.
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.
authors.affiliation: Cancer Research UK London Research Institute (LRI), Clare Hall Laboratories, South Mimms, Herts., UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Boos
authors.forename: Mona
authors.initials: M
authors.lastname: Yekezare
authors.forename: John F X
authors.initials: JF
authors.lastname: Diffley
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018741:Replication Origin
chemical_list: C113571:CDC45 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C547590:GINS1 protein, human; C485931:MTBP protein, human; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; C547406:TICRR protein, human