Cell-cycle-driven noncanonical ubiquitination of METTL14 orchestrates RNA methylation

IF 15.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2026-10-06 DOI:10.1038/s41589-026-02328-5

Jie Cao, Xiner Ying, Lili Zhou, Qingyi Zhang, Chenyang Huang, Tong Dai, Xiao Shu, Minsong Gao, Yujie Mi, Xiaojin Wu, Fengqin Wang, Long Zhang, Fangfang Zhou, Xin-Hua Feng, Jianzhao Liu

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Abstract

The precise temporal control of global mRNA methylation during the cell cycle is critical, yet the underlying mechanism remains unknown. Here we elucidate a noncanonical ubiquitination-mediated regulatory mechanism whereby RLIM deposits predominantly K27-linked ubiquitin (K27-Ub) on the m6A methyltransferase METTL14 in a cell-cycle-programmed manner. This modification modulates enzymatic activity by controlling METTL3–METTL14 complex assembly and RNA substrate engagement, independent of protein stability. We discover that transcriptome-wide mRNA m6A level, K27-Ub intensity on METTL14 and RLIM expression exhibit coordinated periodic oscillations during the cell cycle. Furthermore, this periodic regulation is mediated by CDK1/cyclin B1-directed phosphorylation of RLIM, triggering self-ubiquitination and proteasomal degradation. Functional investigations across multiple models, including human RLIM-knockout cells, myeloid-specific Rlim-knockout mice and participants with acute monocytic leukemia, demonstrate the pathophysiological importance of this previously unrecognized CDK1/cyclin B1–RLIM–METTL14–m6A axis. In summary, our findings identify a cell-cycle-coupled quality control mechanism for epitranscriptomic m6A regulation.

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细胞周期驱动的METTL14非规范泛素化协调RNA甲基化

在细胞周期中，对全局mRNA甲基化的精确时间控制是至关重要的，但其潜在机制尚不清楚。在这里，我们阐明了一种非规范泛素化介导的调节机制，即RLIM以细胞周期编程的方式将k27连接的泛素（K27-Ub）主要沉积在m6A甲基转移酶METTL14上。这种修饰通过控制METTL3-METTL14复合物组装和RNA底物接合来调节酶活性，而不依赖于蛋白质的稳定性。我们发现转录组mRNA m6A水平、METTL14和RLIM表达上的K27-Ub强度在细胞周期中表现出协调的周期性振荡。此外，这种周期性调节是由CDK1/cyclin b1介导的RLIM磷酸化介导的，从而触发自身泛素化和蛋白酶体降解。包括人类rlim敲除细胞、髓系特异性rlim敲除小鼠和急性单核细胞白血病参与者在内的多种模型的功能研究，证明了这一先前未被识别的CDK1/cyclin B1-RLIM-METTL14-m6A轴的病理生理学重要性。总之，我们的研究结果确定了细胞周期耦合的质量控制机制，用于表转录组m6A调控。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.