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dc.titleHP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24 -deficient cells
dc.contributor.authorLiu, J.
dc.contributor.authorYin, X.
dc.contributor.authorLiu, B.
dc.contributor.authorZheng, H.
dc.contributor.authorZhou, G.
dc.contributor.authorGong, L.
dc.contributor.authorLi, M.
dc.contributor.authorLi, X.
dc.contributor.authorWang, Y.
dc.contributor.authorHu, J.
dc.contributor.authorKrishnan, V.
dc.contributor.authorZhou, Z.
dc.contributor.authorWang, Z.
dc.identifier.citationLiu, 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.
dc.description.abstractHeterochromatin 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.
dc.subjectCellular senescence
dc.subjectChromatin remodeling
dc.subjectDNA damage
dc.subjectLamin A
dc.description.sourcetitleCell Cycle
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