title: Identification of genes that are essential to restrict genome duplication to once per cell division.
abstract: Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor to preventing EDR, and in the presence of an apoptosis inhibitor to reveal the full extent of EDR. The results revealed 42 genes that prevented either DNA re-replication or unscheduled endoreplication. All of them participate in one or more of eight cell cycle events. Seventeen of them have not been identified previously in this capacity. Remarkably, 14 of the 42 genes have been shown to prevent aneuploidy in mice. Moreover, suppressing a gene that prevents EDR increased the ability of the chemotherapeutic drug Paclitaxel to induce EDR, suggesting new opportunities for synthetic lethalities in the treatment of human cancers.
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Vassilev
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.|Current address: NantBioscience, Culver City, CA 90232, USA.
authors.forename: Chrissie Y
authors.initials: CY
authors.lastname: Lee
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Vassilev
authors.affiliation: Department of Biochemistry and Molecular Biology, George Washington University, Washington DC 20037, USA.
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhu
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Pinar
authors.initials: P
authors.lastname: Ormanoglu
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.|Current Address: Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Martin
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.
authors.forename: Melvin L
authors.initials: ML
authors.lastname: DePamphilis
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002455:Cell Division / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics
keywords: DNA re-replication; aneuploidy; cell cycle regulation; endoreplication; polyploidy