Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-0148, USA.
J Clin Invest. 2011 Jul;121(7):2833-44. doi: 10.1172/JCI43578. Epub 2011 Jun 13.
Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.
亨廷顿氏舞蹈症-早老综合征（HGPS）是一种破坏性的早老疾病，由 lamin A 基因（LMNA）的点突变引起。该突变持续激活一个隐蔽的剪接供体位点，导致一种称为 progerin 的突变 lamin A 蛋白。最近的研究表明，progerin 也在正常人类细胞和组织中以低水平产生。然而，正常个体中正常衰老和 progerin 产生之间的因果关系尚未确定。在这项研究中，我们在正常人类成纤维细胞中表明，细胞衰老过程中进行性端粒损伤在激活 progerin 产生中起因果作用。进行性端粒损伤也导致多个其他基因的可变剪接发生广泛变化。有趣的是，在不涉及端粒缩短的细胞衰老过程中，并未观察到 progerin 产生的升高。总之，我们的结果表明，在诱导细胞衰老过程中，端粒功能障碍和 progerin 产生之间存在协同关系，为 progerin 如何参与正常衰老过程提供了机制见解。
