Hutchinson–Gilford progeria is a premature aging syndrome caused by a truncated form of lamin A called progerin. Progerin expression results in a variety of cellular defects including heterochromatin loss, DNA damage, impaired proliferation and premature senescence. It remains unclear how these different progerin‐induced phenotypes are temporally and mechanistically linked. To address these questions, we use a doxycycline‐inducible system to restrict progerin expression to different stages of the cell cycle. We find that progerin expression leads to rapid and widespread loss of heterochromatin in G1‐arrested cells, without causing DNA damage. In contrast, progerin triggers DNA damage exclusively during late stages of DNA replication, when heterochromatin is normally replicated, and preferentially in cells that have lost heterochromatin. Importantly, removal of progerin from G1‐arrested cells restores heterochromatin levels and results in no permanent proliferative impediment. Taken together, these results delineate the chain of events that starts with progerin expression and ultimately results in premature senescence. Moreover, they provide a proof of principle that removal of progerin from quiescent cells restores heterochromatin levels and their proliferative capacity to normal levels.

中文翻译：

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异染色质丧失是Hutchinson-Gilford早衰症中早老素诱导的DNA损伤的决定因素。

Hutchinson–Gilford早衰症是一种过早的衰老综合症，是由一种称为progerin的截短形式的Lamin A引起的。早春蛋白表达导致多种细胞缺陷，包括异染色质丢失，DNA损伤，增殖受损和过早衰老。尚不清楚这些不同的早衰素诱导的表型在时间和机理上如何关联。为了解决这些问题，我们使用了强力霉素诱导系统，将早孕素的表达限制在细胞周期的不同阶段。我们发现，progerin的表达导致被G1阻滞的细胞中异染色质快速广泛分布丧失，而不会引起DNA损伤。相反，早老蛋白仅在正常复制异染色质时在DNA复制的后期才触发DNA损伤，并且优先在失去异染色质的细胞中触发。重要的是，从停滞在G1的细胞中去除早老蛋白可恢复异染色质水平，并且不会造成永久性增殖障碍。综上所述，这些结果勾勒出了一系列事件，这些事件始于progerin表达，并最终导致过早衰老。而且，它们提供了原理上的证明，即从静止细胞中除去早老蛋白可将异染色质水平及其增殖能力恢复到正常水平。