CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation.
CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation.
复制标题
DOI：
10.1016/j.celrep.2023.113197
复制
发表时间：
2023-09
期刊：
影响因子：
8.8
通讯作者：
Susu Liu;Runze Wu;Liutao Chen;Ke Deng;Xin Ou;Xin Lu;Mengxia Li;Chao Liu;Shangwu Chen-Shangwu-Ch
中科院分区：
文献类型：
--
作者：
Susu Liu;Runze Wu;Liutao Chen;Ke Deng;Xin Ou;Xin Lu;Mengxia Li;Chao Liu;Shangwu Chen-Shangwu-Ch
由于选择性多聚腺苷酸化（阿帕），癌细胞通常表现出缩短的3′非翻译区（UTR），以促进细胞增殖和迁移。上调的CPSF 6导致3′ UTR的系统性延长，但肿瘤中的CPSF 6表达通常高于健康组织。这种相互矛盾的观察结果表明，有必要研究CPSF 6调节癌症中阿帕转换的潜在机制。在这里，我们发现CPSF 6可以进行液-液相分离（LLPS），并且LLPS升高与远端poly（A）位点的优先使用相关。CLK 2是一种在癌细胞中上调的激酶，通过磷酸化其精氨酸/丝氨酸样结构域破坏CPSF 6 LLPS。CPSF 6 LLPS的减少可导致细胞周期相关基因的3′ UTR缩短，促进细胞增殖。这些结果表明，CPSF 6 LLPS，而不是其表达水平，可能是负责癌细胞中的阿帕调节。
Cancer cells usually exhibit shortened 3′ untranslated regions (UTRs) due to alternative polyadenylation (APA) to promote cell proliferation and migration. Upregulated CPSF6 leads to a systematic prolongation of 3′ UTRs, but CPSF6 expression in tumors is typically higher than that in healthy tissues. This contradictory observation suggests that it is necessary to investigate the underlying mechanism by which CPSF6 regulates APA switching in cancer. Here, we find that CPSF6 can undergo liquid-liquid phase separation (LLPS), and elevated LLPS is associated with the preferential usage of the distal poly(A) sites. CLK2, a kinase upregulated in cancer cells, destructs CPSF6 LLPS by phosphorylating its arginine/serine-like domain. The reduction of CPSF6 LLPS can lead to a shortened 3′ UTR of cell-cycle-related genes and accelerate cell proliferation. These results suggest that CPSF6 LLPS, rather than its expression level, may be responsible for APA regulation in cancer cells.