JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

被引:59
|
作者
Zhao, L. [1 ]
Zhang, Y. [2 ]
Gao, Y. [1 ]
Geng, P. [2 ]
Lu, Y. [2 ]
Liu, X. [1 ]
Yao, R. [1 ]
Hou, P. [2 ]
Liu, D. [3 ]
Lu, J. [2 ]
Huang, B. [1 ]
机构
[1] NE Normal Univ, Minist Educ, Key Lab Mol Epigenet, Changchun 130024, Peoples R China
[2] NE Normal Univ, Inst Cytol & Genet, Changchun 130024, Peoples R China
[3] Univ Auckland, Liggins Inst, Auckland 1, New Zealand
来源
CELL DEATH AND DIFFERENTIATION | 2015年 / 22卷 / 10期
基金
中国国家自然科学基金;
关键词
CELLULAR SENESCENCE; RETINOBLASTOMA PROTEIN; HETEROCHROMATIN FOCI; ONCOGENIC RAS; METHYLATION; BINDING; CYCLE; CONTRIBUTES; PATHWAY; FAMILY;
D O I
10.1038/cdd.2015.6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV(12), and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly.
引用
收藏
页码:1630 / 1640
页数:11
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