Heterochromatin loss as a determinant of progerin-induced DNA damage in Hutchinson-Gilford Progeria
Heterochromatin loss as a determinant of progerin-induced DNA damage in Hutchinson-Gilford Progeria
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DOI：
10.1111/acel.13108
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发表时间：
2020-02-22
期刊：
影响因子：
7.8
通讯作者：
Dreesen, Oliver
中科院分区：
文献类型：
--
作者：
Chojnowski, Alexandre;Ong, Peh Fern;Dreesen, Oliver
Hutchinson-Gilford早老症是一种过早衰老综合征，由一种截短形式的核纤层蛋白A（称为早老蛋白）引起。早老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。目前还不清楚这些不同的早老蛋白诱导的表型是如何在时间和机制上联系起来的。为了解决这些问题，我们使用强力霉素诱导系统来限制早老蛋白的表达到细胞周期的不同阶段。我们发现，早老蛋白的表达导致快速和广泛的损失异染色质在G1期阻滞的细胞，而不造成DNA损伤。相比之下，早老蛋白只在DNA复制的晚期阶段触发DNA损伤，此时异染色质正常复制，并且优先在已经失去异染色质的细胞中。重要的是，从G1期阻滞的细胞中去除早老蛋白可以恢复异染色质水平，并且不会导致永久性的增殖障碍。总之，这些结果描绘了从早老蛋白表达开始并最终导致过早衰老的事件链。此外，它们提供了从静止细胞中去除早老蛋白将异染色质水平和它们的增殖能力恢复到正常水平的原理证明。
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.