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Role of Lamin B1 in Chromatin Instability

机译：Lamin B1在染色质不稳定中的作用

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Nuclear lamins play important roles in the organization and structure of the nucleus; however, the specific mechanisms linking lamin structure to nuclear functions are poorly defined. We demonstrate that reducing nuclear lamin B1 expression by short hairpin RNA-mediated silencing in cancer cell lines to approximately 50% of normal levels causes a delay in the cell cycle and accumulation of cells in early S phase. The S phase delay appears to be due to the stalling and collapse of replication forks. The double-strand DNA breaks resulting from replication fork collapse were inefficiently repaired, causing persistent DNA damage signaling and the assembly of extensive repair foci on chromatin. The expression of multiple factors involved in DNA replication and repair by both nonhomologous end joining and homologous repair is misregulated when lamin B1 levels are reduced. We further demonstrate that lamin B1 interacts directly with the promoters of some genes associated with DNA damage response and repair, including BRCA1 and RAD51. Taken together, the results suggest that the maintenance of lamin B1 levels is required for DNA replication and repair through regulation of the expression of key factors involved in these essential nuclear functions.
机译：核纤层蛋白在核的组织和结构中起着重要作用。然而，将薄层结构与核功能联系起来的具体机制却定义不清。我们证明减少癌细胞系中的短发夹RNA介导的沉默的核纤层蛋白B1表达到正常水平的大约50％会导致细胞周期延迟和早期S期的细胞蓄积。 S阶段的延迟似乎是由于复制叉的停滞和崩溃所致。复制叉塌陷导致的双链DNA断裂效率低下，导致持续的DNA损伤信号传导和染色质上大量修复灶的组装。当层粘连蛋白B1水平降低时，通过非同源末端连接和同源修复参与DNA复制和修复的多种因子的表达被错误调节。我们进一步证明，lamin B1与某些与DNA损伤反应和修复相关的基因的启动子直接相互作用，包括 BRCA1 和 RAD51 。两者合计，结果表明，通过调节参与这些基本核功能的关键因子的表达，DNA的复制和修复需要维持lamin B1的水平。

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