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首页> 外文期刊>Cell cycle >HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24 -deficient cells
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HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24 -deficient cells

机译：HP1α介导有缺陷的异染色质修复并加速Zmpste24缺陷细胞的衰老

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摘要

Heterochromatin protein 1 (HP1) interacts with various proteins, including lamins, to play versatile functions within nuclei, such as chromatin remodeling and DNA repair. Accumulation of prelamin A leads to misshapen nuclei, heterochromatin disorganization, genomic instability, and premature aging in Zmpste24- null mice. Here, we investigated the effects of prelamin A on HP1α homeostasis, subcellular distribution, phosphorylation, and their contribution to accelerated senescence in mouse embryonic fibroblasts (MEFs) derived from Zmpste24-/- mice. The results showed that the level of HP1α was significantly increased in Zmpste24 -/- cells. Although prelamin A interacted with HP1α in a manner similar to lamin A, HP1α associated with the nuclease-resistant nuclear matrix fraction was remarkably increased in Zmpste24-/- MEFs compared with that in wild-type littermate controls. In wild-type cells, HP1α was phosphorylated at Thr50, and the phosphorylation was maximized around 30 min, gradually dispersed 2 h after DNA damage induced by camptothecin. However, the peak of HP1α phosphorylation was significantly compromised and appeared until 2 h, which is correlated with the delayed maximal formation of γ-H2AX foci in Zmpste24-/- MEFs. Furthermore, knocking down HP1α by siRNA alleviated the delayed DNA damage response and accelerated senescence in Zmpste24-/- MEFs, evidenced by the rescue of the delayed γ-H2AX foci formation, downregulation of p16, and reduction of senescenceassociated β -galactosidase activity. Taken together, these findings establish a functional link between prelamin A, HP1α, chromatin remodeling, DNA repair, and early senescence in Zmpste24 -deficient mice, suggesting a potential therapeutic strategy for laminopathy-based premature aging via the intervention of HP1α.
机译：异染色质蛋白1（HP1）与各种蛋白（包括lamins）相互作用，在核内发挥多种功能，例如染色质重塑和DNA修复。在Zmpste24-null小鼠中，prelamin A的积累导致核畸形，异染色质紊乱，基因组不稳定和过早衰老。在这里，我们调查了Prelamin A对HP1α稳态，亚细胞分布，磷酸化及其对源自Zmpste24-/-小鼠的小鼠胚胎成纤维细胞（MEF）加速衰老的影响。结果表明，Zmpste24-/-细胞中HP1α的水平显着升高。尽管前lamin A以类似于层粘连蛋白A的方式与HP1α相互作用，但与野生型同窝对照相比，Zmpste24-/-MEF中与耐核酸酶的核基质组分相关的HP1α显着增加。在野生型细胞中，HP1α在Thr50磷酸化，磷酸化在30分钟左右达到最大，在喜树碱诱导的DNA损伤后2小时逐渐分散。然而，HP1α磷酸化的峰被显着损害，直到2 h才出现，这与Zmpste24-/-MEF中γ-H2AX焦点的最大延迟形成有关。此外，通过siRNA敲低HP1α可以减轻Zmpste24-/-MEFs中延迟的DNA损伤反应并加速衰老，这可以通过挽救延迟的γ-H2AX灶形成，p16的下调以及衰老相关的β-半乳糖苷酶活性的降低来证明。综上所述，这些发现在Zmpste24缺陷小鼠中建立了prelamin A，HP1α，染色质重塑，DNA修复和早期衰老之间的功能性联系，暗示了通过HP1α的干预基于椎板病的过早衰老的潜在治疗策略。

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