METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation

Yongli Shan (), Yanqi Zhang, Yanxing Wei, Cong Zhang, Huaisong Lin, Jiangping He, Junwei Wang, Wenjing Guo, Heying Li, Qianyu Chen, Tiancheng Zhou, Qi Xing, Yancai Liu, Jiekai Chen and Guangjin Pan ()
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Yongli Shan: Chinese Academy of Sciences, Guangzhou Medical University
Yanqi Zhang: Chinese Academy of Sciences, Guangzhou Medical University
Yanxing Wei: Southern Medical University
Cong Zhang: Chinese Academy of Sciences, Guangzhou Medical University
Huaisong Lin: Chinese Academy of Sciences, Guangzhou Medical University
Jiangping He: Guangzhou Laboratory
Junwei Wang: Chinese Academy of Sciences, Guangzhou Medical University
Wenjing Guo: Chinese Academy of Sciences, Guangzhou Medical University
Heying Li: Chinese Academy of Sciences, Guangzhou Medical University
Qianyu Chen: Chinese Academy of Sciences, Guangzhou Medical University
Tiancheng Zhou: Chinese Academy of Sciences, Guangzhou Medical University
Qi Xing: Chinese Academy of Sciences, Guangzhou Medical University
Yancai Liu: Chinese Academy of Sciences, Guangzhou Medical University
Jiekai Chen: Chinese Academy of Sciences, Guangzhou Medical University
Guangjin Pan: Chinese Academy of Sciences, Guangzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Nucleoli are fundamentally essential sites for ribosome biogenesis in cells and formed by liquid-liquid phase separation (LLPS) for a multilayer condensate structure. How the nucleoli integrity is maintained remains poorly understood. Here, we reveal that METTL3/METTL14, the typical methyltransferase complex catalyzing N6-methyladnosine (m6A) on mRNAs maintain nucleoli integrity in human embryonic stem cells (hESCs). METTL3/METTL14 deficiency impairs nucleoli and leads to the complete loss of self-renewal in hESCs. We further show that SUV39H1/H2 protein, the methyltransferases catalyzing H3K9me3 were dramatically elevated in METTL3/METTL14 deficient cells, which causes an accumulation and infiltration of H3K9me3 across the whole nucleolus and impairs the LLPS. Mechanistically, METTL3/METTL14 complex serves as an essential adapter for CRL4 E3 ubiquitin ligase targeting SUV39H1/H2 for polyubiquitination and proteasomal degradation and therefore prevents H3K9me3 accumulation in nucleoli. Together, these findings uncover a previously unknown role of METTL3/METTL14 to maintain nucleoli integrity by facilitating SUV39H1/H2 degradation in human cells.

Date: 2024
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DOI: 10.1038/s41467-024-51742-7

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