Cellular transition to senescence is associated with extensive chromatin reorganization and changes in gene expression. Recent studies appear to imply an association of lamin B1 (LB1) reduction with chromatin rearrangement in human fibroblasts promoted to senescence, while the mechanisms and structural features of these relationships have not yet been clarified. In this work, we examined the functions of LB1 and the lamin B receptor (LBR) in human cancer cells. We found that both LB1 and LBR tend to deplete during cancer cell transfer to senescence by γ-irradiation. A functional study employing silencing of LBR by small hairpin ribonucleic acid (shRNA) constructs revealed reduced LB1 levels suggesting that the regulation of both proteins is interrelated. The reduced expression of LBR resulted in the relocation of centromeric heterochromatin (CSH) from the inner nuclear membrane (INM) to the nucleoplasm and is associated with its unfolding. This indicates that LBR tethers heterochromatin to INM in cycling cancer cells and that LB1 is an integral part of this tethering. Down-regulation of LBR and LB1 at the onset of senescence are thus necessary for the release of heterochromatin binding to lamina, resulting in changes in chromatin architecture and gene expression. However, the senescence phenotype was not manifested in cell lines with reduced LBR and LB1 expression suggesting that other factors, such as deoxyribonucleic acid (DNA) damage, are needed to trigger senescence. We conclude that the primary response of cells to various stresses leading to senescence consists of the down-regulation of LBR and LB1 to attain reversal of the chromatin architecture.
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Research Article|
January 06 2017
Loss of lamin B receptor is necessary to induce cellular senescence
Emilie Lukášová;
1Department of Cell Biology and Radiobiology, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, Brno 61265, Czech Republic
Correspondence: Emilie Lukášová (lukasova@ibp.cz)
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Aleš Kovarˇík;
Aleš Kovarˇík
2Department of Molecular Epigenetics, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, Brno 61265, Czech Republic
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Alena Bacˇíková;
Alena Bacˇíková
1Department of Cell Biology and Radiobiology, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, Brno 61265, Czech Republic
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Martin Falk;
Martin Falk
1Department of Cell Biology and Radiobiology, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, Brno 61265, Czech Republic
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Stanislav Kozubek
Stanislav Kozubek
1Department of Cell Biology and Radiobiology, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, Brno 61265, Czech Republic
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Publisher: Portland Press Ltd
Received:
May 17 2016
Revision Received:
October 17 2016
Accepted:
October 19 2016
Accepted Manuscript online:
October 19 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (2): 281–300.
Article history
Received:
May 17 2016
Revision Received:
October 17 2016
Accepted:
October 19 2016
Accepted Manuscript online:
October 19 2016
Connected Content
A commentary has been published:
Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging
Citation
Emilie Lukášová, Aleš Kovarˇík, Alena Bacˇíková, Martin Falk, Stanislav Kozubek; Loss of lamin B receptor is necessary to induce cellular senescence. Biochem J 15 January 2017; 474 (2): 281–300. doi: https://doi.org/10.1042/BCJ20160459
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