RT Journal Article
SR Electronic
T1 Protein kinase D1 phosphorylates CBX8 to facilitate the disassociation of PRC1 complex from p16 promoter and promotes cell senescence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.09.242891
DO 10.1101/2020.08.09.242891
A1 Yuanyuan Su
A1 Yao Liang
A1 Chenzhong Xu
A1 Na Zhang
A1 Doudou Liu
A1 Guodong Li
A1 Tanjun Tong
A1 Jun Chen
YR 2020
UL http://biorxiv.org/content/early/2020/08/10/2020.08.09.242891.abstract
AB The Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, our knowledge of CBX8 post-translational modifications remains elusive. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Ser256 and Ser311 in an evolutionarily conserved motif. We found that PKD1 activation triggered by serum stimulation, Nocodazole treatment and oncogene Ras-induced cell senescence (Ras OIS) all promotes CBX8 S256/311 phosphorylation. PKD1-mediated CBX8 S256/311 phosphorylation impairs PRC1 complex integrity by reducing the binding of CBX8 to other PRC1 components BMI1 and RING1B, decreases the monoubiquitination of histone H2AK119, and results in CBX8 dissociation from its target INK4a/ARF locus and the de-repression of p16, and thus ultimately facilitates cellular senescence. CBX8 S256/311 phosphorylation also compromises hepatocellular cancer cells proliferation and migration. Collectively, these results suggest that PKD1-mediated CBX8 S256/311 phosphorylation is a key mechanism governing CBX8 function, including cell senescence and cancer cell proliferation.Financial support This work was supported by grants from Ministry of Science and Technology of the People’s Republic of China (2018YFC2000102), and from National Natural Science Foundation of China (31871382 and 81571369).Competing Interest StatementThe authors have declared no competing interest.