State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China.
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China.
Cell Rep. 2023 Oct 31;42(10):113197. doi: 10.1016/j.celrep.2023.113197. Epub 2023 Sep 30.
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.
癌细胞通常由于可变多聚腺苷酸化（APA）而表现出缩短的 3'非翻译区（UTR），以促进细胞增殖和迁移。上调的 CPSF6 导致 3'UTR 的系统延长，但肿瘤中的 CPSF6 表达通常高于健康组织。这一矛盾的观察表明，有必要研究 CPSF6 调节癌症中 APA 转换的潜在机制。在这里，我们发现 CPSF6 可以发生液-液相分离（LLPS），并且升高的 LLPS 与远端 poly(A) 位点的优先使用有关。CLK2 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 CPSF6 的 LLPS。CPSF6 LLPS 的减少会导致与细胞周期相关基因的 3'UTR 缩短，并加速细胞增殖。这些结果表明，CPSF6 LLPS 而不是其表达水平可能是癌细胞中 APA 调节的原因。
