title: Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.
abstract: In all eukaryotic organisms, inappropriate firing of replication origins during the G2 phase of the cell cycle is suppressed by cyclin-dependent kinases. Multicellular eukaryotes contain a second putative inhibitor of re-replication called geminin. Geminin is believed to block binding of the mini-chromosome maintenance (MCM) complex to origins of replication, but the mechanism of this inhibition is unclear. Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading. The inhibition of DNA replication by geminin that is observed in cell-free DNA replication extracts is reversed by the addition of excess Cdt1. In the normal cell cycle, Cdt1 is present only in G1 and S, whereas geminin is present in S and G2 phases of the cell cycle. Together, these results suggest that geminin inhibits inappropriate origin firing by targeting Cdt1.
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors: J A
authors: JA
authors: Wohlschlegel
authors: B T
authors: BT
authors: Dwyer
authors: S K
authors: SK
authors: Dhar
authors: C
authors: C
authors: Cvetic
authors: J C
authors: JC
authors: Walter
authors: A
authors: A
authors: Dutta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002474:Cell-Free System; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019143:Evolution, Molecular; D016193:G1 Phase; D016195:G2 Phase; D064248:Geminin; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011233:Precipitin Tests; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018741:Replication Origin; D016196:S Phase; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C577998:GMNN protein, Xenopus; C577995:GMNN protein, human; D064248:Geminin; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins