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

Yongli ShanYanqi ZhangYanxing WeiCong ZhangHuaisong LinJiangping HeJunwei WangWenjing GuoHeying LiQianyu ChenTiancheng ZhouQi XingYancai LiuJie-Kai ChenGuangjin Pan
Published in: Nature communications (2024)
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 6 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.
Keyphrases
  • induced apoptosis
  • endothelial cells
  • oxidative stress
  • genome wide
  • embryonic stem cells
  • small molecule
  • drug delivery
  • induced pluripotent stem cells
  • mouse model
  • single cell
  • smoking cessation