B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
Yuwen Li1, Xiaodan Ma1, Zhiming Chen1
1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
Nature Communications
|August 24, 2019
Summary
ProMyelocytic Leukemia (PML) protein oligomerization is crucial for nuclear body formation and function. Disrupting PML B1-box interfaces impairs this process and prevents cancer development.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- ProMyelocytic Leukemia (PML) protein forms large nuclear bodies, essential for cellular processes.
- The mechanism governing PML nuclear body assembly has remained unclear.
Purpose of the Study:
- To elucidate the oligomerization mechanism of the PML protein's RBCC domain.
- To investigate the role of PML oligomerization in nuclear body biogenesis and its implications in cancer.
Main Methods:
- Purification of PMLRBCC domain.
- Gel filtration, ultracentrifugation, X-ray crystallography, and Small-Angle X-ray Scattering (SAXS) analyses.
- In vitro and in vivo studies using cell lines (HeLaPml-/-) and transgenic mouse models.
Main Results:
- A sequential oligomerization pathway (monomer, dimer, tetramer, N-mer) for PMLRBCC was identified.
- Structural analysis revealed networking interfaces (W157, F158, SD1) within the B1-box crucial for oligomerization.
- Perturbations in B1 interfaces disrupted in vitro oligomerization, abolished PML sumoylation, and impaired nuclear body formation.
- A specific mutation (PML-RARα F158E) in transgenic mice prevented leukemia development.
- Single-cell RNA sequencing indicated B1 oligomerization regulates PML-RARα-driven transactivation.
Conclusions:
- A novel B1-box-mediated oligomerization mechanism for PML protein has been defined.
- PML oligomerization is a critical factor in nuclear body biogenesis and plays a significant role in carcinogenesis, offering potential therapeutic targets.
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