HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24-deficient cells.

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 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.

• Authors: Jia Liu, Xianhui Yin, Baohua Liu, Huiling Zheng, Guangqian Zhou, Liyun Gong, Meng Li, Xueqin Li, Youya Wang, Jingyi Hu, Vaidehi Krishnan, Zhongjun Zhou, Zimei Wang
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 13 Issue 8 Pg. 1237-47 ( 2014) ISSN: 1551-4005 [Electronic] United States
• PMID: 24584199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromosomal Proteins, Non-Histone
• H2AX protein, mouse
• Heterochromatin
• Histones
• Lamin Type A
• Membrane Proteins
• Nuclear Proteins
• Protein Precursors
• RNA, Small Interfering
• prelamin A
• Chromobox Protein Homolog 5
• Threonine
• DNA
• Metalloendopeptidases
• Zmpste24 protein, mouse

Topics

• Aging, Premature (metabolism)
• Animals
• Cells, Cultured
• Cellular Senescence (genetics)
• Chromobox Protein Homolog 5
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• DNA (metabolism)
• DNA Repair
• Fibroblasts
• Heterochromatin (metabolism)
• Histones (metabolism)
• Lamin Type A
• Membrane Proteins (genetics, metabolism)
• Metalloendopeptidases (genetics, metabolism)
• Mice
• Mice, Knockout
• Nuclear Matrix (metabolism)
• Nuclear Proteins (metabolism)
• Phosphorylation
• Progeria (genetics, metabolism)
• Protein Precursors (metabolism)
• RNA, Small Interfering (metabolism)
• Threonine (metabolism)