Loss of lamin B receptor is necessary to induce cellular senescence

0485752 - BFÚ 2018 GB eng J - Článek v odborném periodiku
Lukášová, Emilie - Kovařík, Aleš - Bačíková, Alena - Falk, Martin - Kozubek, Stanislav
Loss of lamin B receptor is necessary to induce cellular senescence.
Biochemical Journal. Roč. 474 (2017), s. 281-300. ISSN 0264-6021. E-ISSN 1470-8728
Grant CEP: GA ČR GBP302/12/G157; GA ČR GBP501/12/G090
Institucionální podpora: RVO:68081707
Klíčová slova: oncogene-induced senescence * inner nuclear-membrane * dna-damage response
Obor OECD: Genetics and heredity (medical genetics to be 3)
Impakt faktor: 3.857, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0280696