title: 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.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Yin
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China; Deparment of Biochemistry; LKS Faculty of Medicine; The University of Hong Kong; Pokfulam, Hong Kong.
authors.forename: Baohua
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Aging Research; Guangdong Medical College; Dong-guan, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Guangqian
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Gong
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Li
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Youya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Cancer Science Institute of Singapore; National University of Singapore; Singapore.
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Deparment of Biochemistry; LKS Faculty of Medicine; The University of Hong Kong; Pokfulam, Hong Kong.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Deparment of Biochemistry and Molecular Biology; Health Science Center; Shenzhen University, P.R. China.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wang
mesh_terms: D019588:Aging, Premature / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D005347:Fibroblasts; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D034904:Lamin Type A; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015530:Nuclear Matrix / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011371:Progeria / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
chemical_list: D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D006570:Heterochromatin; D006657:Histones; D034904:Lamin Type A; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D009687:Nuclear Proteins; D011498:Protein Precursors; D034741:RNA, Small Interfering; D013912:Threonine; C090764:prelamin A; C491250:Zmpste24 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: DNA damage; HP1; cellular senescence; chromatin remodeling; lamin A; progeria