METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation
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 (m<sup>6</sup>A) 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.
Authors
- Yancai Liu
- Jiekai Chen (ORCID: https://orcid.org/0000-0001-5168-7074)
- Guangjin Pan (ORCID: https://orcid.org/0000-0002-2378-7198)
- Jiangping He (ORCID: https://orcid.org/0000-0002-1425-3530)
- Heying Li (ORCID: https://orcid.org/0009-0006-5025-8941)
- Huaisong Lin
- Cong Zhang (ORCID: https://orcid.org/0009-0009-7547-5119)
- Junwei Wang (ORCID: https://orcid.org/0000-0001-9764-9524)
- Yanqi Zhang (ORCID: https://orcid.org/0000-0001-6896-8657)
- Qianyu Chen (ORCID: https://orcid.org/0000-0002-4098-5735)
- Yanxing Wei (ORCID: https://orcid.org/0000-0003-2156-0835)
- Qi Xing (ORCID: https://orcid.org/0000-0001-9898-7840)
- Yongli Shan
- Tiancheng Zhou
- Wenjing Guo
Institutions
- Department of Health (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Nanfang Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41467-024-51742-7
- Citations
- 17
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- China Postdoctoral Science Foundation
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- University of Chinese Academy of Sciences
- University of Chinese Academy of Sciences Education Foundation
- National Key Research and Development Program of China
- Science and Technology Planning Project of Guangdong Province
- Youth Innovation Promotion Association
- National Key Research and Development Program of China Stem Cell and Translational Research
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences