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Echchgadda I Song CS Oh T Ahmed M De La Cruz IJ Chatterjee B 《Molecular endocrinology (Baltimore, Md.)》2007,21(9):2099-2111
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Neal A. Englert George Luo Joyce A. Goldstein Sailesh Surapureddi 《The Journal of biological chemistry》2015,290(4):2264-2278
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Rauen T Hedrich CM Juang YT Tenbrock K Tsokos GC 《The Journal of biological chemistry》2011,286(50):43437-43446
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Jia Liu Xianhui Yin Baohua Liu Huiling Zheng Guangqian Zhou Liyun Gong 《Cell cycle (Georgetown, Tex.)》2014,13(8):1237-1247
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 senescence-associated 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. 相似文献