title: RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence.
abstract: The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase-regulated nuclear-cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran⋅GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran⋅GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage-induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin β-dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ran⋅GTP-regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ran⋅GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage.
authors: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Pavol
authors: P
authors: Cekan
authors: Department of Physics, Grinnell College, Grinnell, IA 50112 Physiology Course, Marine Biological Laboratory, Woods Hole, MA 02543.
authors: Keisuke
authors: K
authors: Hasegawa
authors: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Yu
authors: Y
authors: Pan
authors: Physiology Course, Marine Biological Laboratory, Woods Hole, MA 02543 Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.
authors: Emily
authors: E
authors: Tubman
authors: Physiology Course, Marine Biological Laboratory, Woods Hole, MA 02543 Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.
authors: David
authors: D
authors: Odde
authors: Collaborative Protein Technology Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Jin-Qiu
authors: JQ
authors: Chen
authors: Collaborative Protein Technology Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Michelle A
authors: MA
authors: Herrmann
authors: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Sheetal
authors: S
authors: Kumar
authors: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 pkalab@yahoo.com.
authors: Petr
authors: P
authors: Kalab
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D045325:HCT116 Cells / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D028961:beta Karyopherins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D004317:Doxorubicin; D020662:Guanine Nucleotide Exchange Factors; D006160:Guanosine Triphosphate; D028884:Karyopherins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D028961:beta Karyopherins; D020931:ran GTP-Binding Protein; D000097606:Exportin 1 Protein; C120587:RAN protein, human; C062521:RCC1 protein, human