METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation
Summary
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. © 2024. The Author(s).
| Authors | Shan Y, Zhang Y, Wei Y, Zhang C, Lin H, He J, Wang J, Guo W, Li H, Chen Q, Zhou T, Xing Q, Liu Y, Chen J, Pan G |
|---|---|
| Journal | Nature communications |
| Publication Date | 2024 Aug 21;15(1):7186 |
| PubMed | 39169036 |
| PubMed Central | PMC11339338 |
| DOI | 10.1038/s41467-024-51742-7 |