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On March 29, professor Meng Guoyu from RuijinHospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, and professor Hugues de The from France, published an article entitled “RING tetramerization is required for nuclear body biogenesis and PML sumoylation” in Nature Communications. The latest research is about the molecular level reveals the PML nuclear body assembly mechanism and PML itself the SUMO modified the structure of the foundation. It was found that PML-RING polymerization was of great significance to the pathogenesis and targeted treatment of acute promyelocytic leukemia (APL).
PML (promyelocytic leukemia) nucleus is a super-protein complex with PML protein as the main skeleton component, located in the nucleus and about 0.1-2 m in diameter. PML nuclear body positioning in the function of many proteins (such as P53, UBC9, etc.), gives the PML nuclear body‘s ability to participate in the modulation of cell biology process important: genome stability control, transcriptional regulation, protein modification after translation, cell senescence and apoptosis regulation, dry stem cells maintain and angiogenesis regulation, etc. The study of PML has been a hot topic in the field of life science. In recent years, new functions of PML nucleosomes have been discovered. At present, studies at home and abroad mainly focus on functional exploration of PML nucleosomes, such as new findings of PML nucleosomes in the occurrence and treatment of solid tumors. However, since there have been no reports on the structure of PML and PML nucleosomes, the assembly mechanism of this super protein complex has been a difficult problem in the field of PML.
APL was once the most dangerous acute leukemia due to its short course of onset and severe hemorrhagic disease. The discovery of targeted drugs, total trans-retinoic acid (ATRA) and arsenic trioxide (ATO), has made the 5-year disease-free survival rate of APL patients reach more than 90% and become a precedent and model for successful targeted therapy. Studies on the pathogenesis and targeted therapeutic mechanism of APL can provide theoretical basis and clinical reference for the research and treatment of leukemia and other tumors. APL is mostly accompanied by t(15) in cytogenetics. 17) (q22; Q21) chromosome translocation, producing PML/RARA fusion gene. PML/RARA fusion protein causes transcription inhibition of target genes related to granulocyte differentiation. PML/RARA interacts with wild-type PML, resulting in the destruction of the normal structure of the PML nucleus. Both play an important role in the development of APL. However, because lack of structural biology related information, for the pathogenesis of the molecular level, and the important details of ATRA treatment/ATO now is not very clear, so for PML/RARA structural biology research becomes very urgent and important.
The team used X-ray crystal diffraction (XRD) to successfully analyze the structure of the PML RING domain. Through biophysics, cell and molecular biology analysis found that PML (RING) mediated PML four polymers of PML nuclear body assembly play a crucial role: PML (RING four polymers is the key step in the PML nuclear body assembly, only after the PML aggregation is the SUMO modification, thus raising contains the SUMO effect element of protein and other related partners assembled into mature PML nuclear body. The PML RING tetramer structure is the first time in nearly 20 years that people have observed how PML proteins oligomeric to form PML nucleosomes at the atomic level. The discovery is also the first reported biomolecular tetrameric structure in the RING protein family to date.
At the same time, it also have a positive clinical significance, the research team found by biochemical and animal experiment, the onset of PML (RING) polymerization of APL and targeted therapy has very important influence. This is another important discovery and extension in APL field of Shanghai hematology research institute, providing a new theory for leukemia treatment and prognosis.