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RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence

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 R...

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Autores principales: Cekan, Pavol, Hasegawa, Keisuke, Pan, Yu, Tubman, Emily, Odde, David, Chen, Jin-Qiu, Herrmann, Michelle A., Kumar, Sheetal, Kalab, Petr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831887/
https://www.ncbi.nlm.nih.gov/pubmed/26864624
http://dx.doi.org/10.1091/mbc.E16-01-0025
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author Cekan, Pavol
Hasegawa, Keisuke
Pan, Yu
Tubman, Emily
Odde, David
Chen, Jin-Qiu
Herrmann, Michelle A.
Kumar, Sheetal
Kalab, Petr
author_facet Cekan, Pavol
Hasegawa, Keisuke
Pan, Yu
Tubman, Emily
Odde, David
Chen, Jin-Qiu
Herrmann, Michelle A.
Kumar, Sheetal
Kalab, Petr
author_sort Cekan, Pavol
collection PubMed
description 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.
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spelling pubmed-48318872016-06-30 RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence Cekan, Pavol Hasegawa, Keisuke Pan, Yu Tubman, Emily Odde, David Chen, Jin-Qiu Herrmann, Michelle A. Kumar, Sheetal Kalab, Petr Mol Biol Cell Articles 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. The American Society for Cell Biology 2016-04-15 /pmc/articles/PMC4831887/ /pubmed/26864624 http://dx.doi.org/10.1091/mbc.E16-01-0025 Text en © 2016 Cekan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Cekan, Pavol
Hasegawa, Keisuke
Pan, Yu
Tubman, Emily
Odde, David
Chen, Jin-Qiu
Herrmann, Michelle A.
Kumar, Sheetal
Kalab, Petr
RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title_full RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title_fullStr RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title_full_unstemmed RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title_short RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence
title_sort rcc1-dependent activation of ran accelerates cell cycle and dna repair, inhibiting dna damage–induced cell senescence
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831887/
https://www.ncbi.nlm.nih.gov/pubmed/26864624
http://dx.doi.org/10.1091/mbc.E16-01-0025
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