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Loss of lamin B receptor is necessary to induce cellular senescence
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SYSNO ASEP 0485752 Document Type J - Journal Article R&D Document Type The record was not marked in the RIV Subsidiary J Článek ve WOS Title Loss of lamin B receptor is necessary to induce cellular senescence Author(s) Lukášová, Emilie (BFU-R) RID, ORCID
Kovařík, Aleš (BFU-R) RID, ORCID
Bačíková, Alena (BFU-R)
Falk, Martin (BFU-R) RID, ORCID
Kozubek, Stanislav (BFU-R) RIDNumber of authors 5 Source Title Biochemical Journal. - : Portland Press - ISSN 0264-6021
Roč. 474 (2017), s. 281-300Number of pages 20 s. Publication form Print - P Language eng - English Country GB - United Kingdom Keywords oncogene-induced senescence ; inner nuclear-membrane ; dna-damage response Subject RIV EB - Genetics ; Molecular Biology OECD category Genetics and heredity (medical genetics to be 3) R&D Projects GBP302/12/G157 GA ČR - Czech Science Foundation (CSF) GBP501/12/G090 GA ČR - Czech Science Foundation (CSF) Institutional support BFU-R - RVO:68081707 UT WOS 000393766200006 DOI 10.1042/BCJ20160459 Annotation 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 gamma-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. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2018
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