The cellular transition to senescence is associated with extensive chromatin reorganization and gene expression changes. Recent studies appeared implying an association of lamin B1 (LB1) reduction with chromatin rearrangement in human fibroblasts promoted to senescence, while the mechanisms and structural features of these relations were not yet clarified. In this work we examined the functions of LB1 and lamin B receptor (LBR) in human cancer cells. We found that both LB1 and LBR tend to deplete during cancer cells transfer to senescence by γ-irradiation. A functional study employing silencing of LBR by shRNA constructs revealed reduced LB1 levels suggesting that regulation of both proteins is interrelated. Reduced expression of LBR resulted in the relocation of centromeric heterochromatin (CSH) from the inner nuclear membrane (INM) to nucleoplasm associated with its unfolding. It indicates that LBR tethers heterochromatin to INM in cycling cancer cells and that LB1 is an integral part to this tethering. Down-regulations of LBR and LB1 at the onset of senescence are thus necessary for the release of heterochromatin from binding to the lamina, resulting in changes in chromatin architecture and gene expression. However, senescence phenotype was not manifested in lines with reduced LBR and LB1 expression suggesting that other factors such as the DNA damage are needed for senesce trigger. We conclude that the primary response of cells to various stresses leading to senescence consists in down-regulation of LBR and LB1 to attain reversal of chromatin architecture.
- Lamin B1
- heterochromatin tether
- centromeric heterochromatin
- ; chromatin architecture
- centromeric heterochromatin relocation and distension
- ©2016 The Author(s)
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