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|Title:||HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24 -deficient cells|
|Citation:||Liu, J., Yin, X., Liu, B., Zheng, H., Zhou, G., Gong, L., Li, M., Li, X., Wang, Y., Hu, J., Krishnan, V., Zhou, Z., Wang, Z. (2014-04-15). HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24 -deficient cells. Cell Cycle 13 (8) : 1237-1247. ScholarBank@NUS Repository. https://doi.org/10.4161/cc.28105|
|Abstract:||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. © 2014 Landes Bioscience.|
|Source Title:||Cell Cycle|
|Appears in Collections:||Staff Publications|
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