Abstract
The nuclear lamins play important roles in the structural organization and function of the metazoan cell nucleus. Recent studies on B-type lamins identified a requirement for lamin B1 (LB1) in the regulation of cell proliferation in normal diploid cells. In order to further investigate the function of LB1 in proliferation, we disrupted its normal expression in U-2 OS human osteosarcoma and other tumor cell lines. Silencing LB1 expression induced G1 cell cycle arrest without significant apoptosis. The arrested cells are unable to mount a timely and effective response to DNA damage induced by UV irradiation. Several proteins involved in the detection and repair of UV damage by the nucleotide excision repair (NER) pathway are down-regulated in LB1 silenced cells including DDB1, CSB and PCNA. We propose that LB1 regulates the DNA damage response to UV irradiation by modulating the expression of specific genes and activating persistent DNA damage signaling. Our findings are relevant to understanding the relationship between the loss of LB1 expression, DNA damage signaling, and replicative senescence.
Highlights
The nuclear lamins are type V intermediate filament proteins found primarily within the nucleus of metazoan cells
Expression analysis of nucleotide excision repair (NER), cell cycle regulation and DNA damage detection factors in lamin B1 (LB1) silenced and control cells. mRNA from Sc and shLB1 U-2 OS cells was prepared at 3 days after silencing and analyzed by qRT-PCR using GAPDH as a reference gene
We show that decreasing the levels of LB1 in human tumor cell lines by shRNA-mediated silencing leads to a G1 cell cycle arrest
Summary
The nuclear lamins are type V intermediate filament proteins found primarily within the nucleus of metazoan cells. The lamins play important roles in providing mechanical support and shape to the nucleus and in regulating many nuclear functions including DNA replication, Pol II transcription, DNA repair, mitotic spindle formation, response to oxidative stress, and chromosome positioning [1]. The mechanisms by which lamins mediate these functions remain largely unknown. LA and LC are expressed in developmentally regulated patterns from a single gene by alternative splicing. In contrast LB1 and LB2 are expressed from two different genes, with at least one B-type lamin being expressed in all cell types throughout development and differentiation [2]
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