Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.
Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.
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DOI：
10.7554/elife.07759
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发表时间：
2015-08-27
期刊：
影响因子：
7.7
通讯作者：
Dreesen O
中科院分区：
文献类型：
--
作者：
Chojnowski A;Ong PF;Wong ES;Lim JS;Mutalif RA;Navasankari R;Dutta B;Yang H;Liow YY;Sze SK;Boudier T;Wright GD;Colman A;Burke B;Stewart CL;Dreesen O
Hutchinson-Gilford progeria（HGPS）是一种由LMNA突变引起的过早衰老综合征，导致一种截短形式的核纤层蛋白A，称为progerin。早老蛋白触发异染色质标记物H3 K27 me 3的丢失，以及通过端粒酶防止的过早衰老。然而，早老蛋白导致疾病的机制仍不清楚。在这里，我们描述了一个可诱导的细胞系统来模拟HGPS，并发现LAP 2 α（lamina-associated polypeptide-α）与lamin A相互作用，而其与progerin的相互作用显著降低。超分辨率显微镜显示，超过50%的端粒定位于板层，LAP 2 α与端粒的关联在HGPS中受损。这种受损的相互作用是HGPS的核心，因为增加LAP 2 α水平挽救了早老蛋白诱导的增殖缺陷和H3 K27 me 3的丢失，而降低LAP 2水平则加剧了早老蛋白诱导的缺陷。这些发现提供了新的见解HGPS的病理生理基础，以及如何核纤层调节增殖和染色质组织。http://dx.doi.org/10.7554/eLife.07759.001 Hutchinson-Gilford早衰症（HGPS）是一种罕见的遗传性疾病，个体过早衰老。新生儿在出生时看起来很正常，但在一岁左右就开始迅速衰老。这种疾病的症状包括发育迟缓和关节僵硬，患者往往在青少年时期死于心力衰竭。一种叫做核纤层蛋白A的蛋白质的突变版本导致HGPS;这种突变体被称为早老蛋白。在产生早老蛋白的细胞中，保护染色体末端（包含大部分细胞DNA的结构）免受损伤的“端粒”异常短。每次细胞分裂，端粒就会变短。如果它们变得太短，DNA就会受损，细胞停止分裂并进入一种称为衰老的状态。HGPS对人体某些组织的影响比其他组织更严重，这些组织往往会产生高水平的早老蛋白。通过逐渐提高人类细胞中早老蛋白的水平，Chojnowski等人发现，只有当细胞中早老蛋白的量超过特定阈值时，DNA损伤和细胞衰老才会发生。此外，端粒聚合酶的表达-一种可以延长端粒的复合物-防止了早老素诱导的DNA损伤和过早衰老。为了找出progerin如何影响细胞，Chojnowski等人比较了核纤层蛋白A和progerin如何与其他蛋白质相互作用。这表明早老蛋白与一种名为LAP 2 α的蛋白质的相互作用比核纤层蛋白A弱。LAP 2 α通常与端粒相关，但使用超高分辨率显微镜，Chojnowski等人观察到这种关联不太可能发生在HGPS患者的细胞中。重要的是，增加表达早老蛋白的细胞中LAP 2 α的量可以防止DNA损伤和衰老，并使这些细胞能够继续分裂。Chojnowski等人提出，在HGPS中，LAP 2 α和早老蛋白之间的弱相互作用破坏了LAP 2 α与端粒的相互作用，从而阻止细胞分裂。了解这一过程可能有助于设计治疗HGPS的新方法，也可能有助于我们了解由核纤层蛋白突变引起的其他疾病。DOI：http://dx.doi.org/10.7554/eLife.07759.002网站
Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization. DOI: http://dx.doi.org/10.7554/eLife.07759.001 Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disease in which individuals age prematurely. Newborns appear normal at birth, but start ageing rapidly when they are around a year old. Symptoms of the disease include stunted growth and joint stiffness, and individuals often die of heart failure during their teens. A mutated version of a protein called lamin A causes HGPS; this mutant is known as progerin. In cells that produce progerin, the ‘telomeres’ that protect the ends of chromosomes (the structures that contain most of the cell's DNA) from damage, are unusually short. Every time a cell divides, the telomeres get shorter. If they get too short, the DNA is damaged and the cell stops dividing and enters a state known as senescence. HGPS affects some of the tissues in the body more severely than others, and these tissues tend to produce high levels of progerin. By gradually raising the levels of progerin in human cells, Chojnowski et al. found that DNA damage and cell senescence only occur when the amount of progerin in a cell exceeds a particular threshold. Moreover, the expression of telomerase—a complex that can elongate telomeres—prevented progerin-induced DNA damage and premature senescence. To find out how progerin affects cells, Chojnowski et al. compared how lamin A and progerin interact with other proteins. This revealed that progerin interacts with a protein called LAP2α more weakly than lamin A. LAP2α normally associates with telomeres, but using super-high resolution microscopy, Chojnowski et al. observed that this association is less likely to occur in the cells of people with HGPS. Importantly, increasing the amount of LAP2α in progerin-expressing cells prevented DNA damage and senescence and enabled these cells to continue dividing. Chojnowski et al. propose that in HGPS, the weak interaction between LAP2α and progerin disrupts how LAP2α interacts with telomeres, which prevents cells from dividing. Understanding this process may help to design new ways of treating HGPS, and may also help us to understand other diseases that are caused by mutations in lamin proteins. DOI: http://dx.doi.org/10.7554/eLife.07759.002