Pan Qimei, Luo Peng, Qiu Yuntan, Hu Kaishun, Lin Lehang, Zhang Heyun, Yin Dong, Shi Chunmeng
Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University, Chongqing, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Cell Death Differ. 2025 Feb 27. doi: 10.1038/s41418-025-01465-z.
Numerous genes exhibit periodic oscillations in mRNA expression, essential for orderly cell division. Mitosis-related mRNAs fluctuate cyclically from the G2 to M phase, primarily regulated by transcription factors. However, the role of post-transcriptional regulation in this process remains unclear. Here, we demonstrated a decrease in mRNA levels of centromere protein F (CENPF) from the early to late G2 phase. SETDB1-PC4-UPF1 serves as a crucial post-transcriptional machinery, orchestrating the periodic degradation of CENPF mRNA, ensuring balanced CENP expression, proper spindle assembly, and successful mitosis. In early G2, newly synthesized CENPF mRNAs accumulate and bind to PC4, leading to SETDB1-mediated PC4 dimethylation at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of CENPF mRNAs, forming a regulatory loop for CENP homeostasis. Elevated PC4 dimethylation in hepatocellular carcinoma, coupled with increased sensitivity to taxanes upon its inhibition, suggests promising therapeutic avenues. These findings suggest a post-transcriptional quality control mechanism regulating cyclic mitotic mRNA fluctuations, providing comprehensive insights into cell cycle gene regulation dynamics.
许多基因在mRNA表达上呈现周期性振荡，这对细胞有序分裂至关重要。与有丝分裂相关的mRNA从G2期到M期呈周期性波动，主要受转录因子调控。然而，转录后调控在这一过程中的作用仍不清楚。在此，我们证明了从G2早期到晚期，着丝粒蛋白F（CENPF）的mRNA水平下降。SETDB1-PC4-UPF1作为一种关键的转录后机制，协调CENPF mRNA的周期性降解，确保CENP表达平衡、纺锤体正确组装和有丝分裂成功进行。在G2早期，新合成的CENPF mRNA积累并与PC4结合，导致SETDB1介导PC4在K35处发生二甲基化。在G2晚期，二甲基化的PC4与UPF1相互作用，促进CENPF mRNA的去腺苷酸化依赖性降解，形成CENP稳态的调节环。肝细胞癌中PC4二甲基化升高，且抑制PC4后对紫杉烷的敏感性增加，提示了有前景的治疗途径。这些发现表明存在一种调节有丝分裂mRNA周期性波动的转录后质量控制机制，为细胞周期基因调控动态提供了全面的见解。
