HP1? mediates defective heterochromatin repair and accelerates senescence in Zmpste24-deficient cells.
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 HP1? 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 HP1? was significantly increased in Zmpste24(-/-) cells. Although prelamin A interacted with HP1? in a manner similar to lamin A, HP1? 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, HP1? 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 HP1? phosphorylation was significantly compromised and appeared until 2 h, which is correlated with the delayed maximal formation of ?-H2AX foci in Zmpste24(-/-) MEFs. Furthermore, knocking down HP1? by siRNA alleviated the delayed DNA damage response and accelerated senescence in Zmpste24(-/-) MEFs, evidenced by the rescue of the delayed ?-H2AX foci formation, downregulation of p16, and reduction of senescence-associated ?-galactosidase activity. Taken together, these findings establish a functional link between prelamin A, HP1?, 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 HP1?.