Related Experiment Video

Updated: Oct 2, 2025

Chemical Dimerization-Induced Protein Condensates on Telomeres
08:52

Chemical Dimerization-Induced Protein Condensates on Telomeres

Published on: April 12, 2021

3.2K

Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate

Xuejing Shao1, Yingqian Chen1, Aixiao Xu1

  • 1Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Cell Death and Differentiation
|February 23, 2022
PubMed

Insights

Neddylation disrupts PML nuclear bodies in acute promyelocytic leukemia (APL) by altering PML/RARα phase separation. Inhibiting neddylation with MLN4924 eradicates APL cells, offering a new therapeutic strategy.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Acute promyelocytic leukemia (APL) is driven by the PML/RARα oncoprotein.
  • PML/RARα disrupts PML nuclear bodies (NBs), which are crucial for tumor suppression.
  • The precise mechanisms underlying PML NB disruption in APL are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PML/RARα disrupts PML nuclear bodies in APL.
  • To investigate the role of neddylation in the aberrant phase separation of PML/RARα.
  • To evaluate the therapeutic potential of targeting neddylation in APL.

Main Methods:

  • Investigated the phase separation properties of PML/RARα.
  • Analyzed the effect of neddylation on PML/RARα DNA-binding and phase separation.
  • Utilized pharmacological inhibition of neddylation (MLN4924) in vitro and in vivo APL models.

Main Results:

  • Neddylation of PML/RARα in the RARα moiety enhances DNA binding and disrupts PML NB assembly via aberrant phase separation.
  • Deneddylation of PML/RARα restores phase separation, reconstructs functional NBs, and activates tumor-suppressive signaling.
  • MLN4924 treatment effectively eradicated APL cells in both in vitro and in vivo experimental settings.

Conclusions:

  • Neddylation-induced phase separation defects of PML/RARα are a key mechanism for PML NB disruption in APL.
  • Targeting the neddylation pathway presents a promising therapeutic strategy for APL eradication.
  • Restoring PML NB integrity through deneddylation suppresses leukemogenesis.

More Related Videos

Visualization of Replisome Encounters with an Antigen Tagged Blocking Lesion08:24

Visualization of Replisome Encounters with an Antigen Tagged Blocking Lesion

Published on: July 27, 2021

1.5K
Assays for the Degradation of Misfolded Proteins in Cells10:56

Assays for the Degradation of Misfolded Proteins in Cells

Published on: August 28, 2016

12.2K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.7K
Disassembly of Intermediate Filaments01:35

Disassembly of Intermediate Filaments

Intermediate filaments (IFs) do not undergo spontaneous disassembly. Enzymes, kinases, and phosphatases add and remove phosphates from specific sites to regulate their disassembly. The IF concentration in the cytoplasm also regulates the disassembly. If the concentration crosses a threshold, it activates the protein kinases in the vicinity, allowing the phosphorylation of IFs.
Keratin proteins, found at the cell periphery near cell junctions, undergo a cycle of assembly and disassembly. In Type...
2.2K
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.0K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
3.0K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
36.4K
DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.4K