There are many different factors in a person's illness, but there are two types of internal and external causes. The most fundamental of the intrinsic factors is the genes. Medical research shows that all diseases are more or less related to genes, mainly due to mutations in gene expression. How does the regulation of gene expression control the development of organisms, and how does it affect the health and disease of the human body? This is a hot topic for scientists from all over the world to compete in research.
Recently, a study by Prof. Long Jiafu, a team of professors of the State Key Laboratory of Medicinal Chemistry Biology, School of Life Sciences, Nankai University, revealed an important protein complex that affects the regulation of gene expression, the Paf1-Ctr9 subcomplex in the Paf1 complex. The mystery of assembly and functional regulation lays the molecular foundation for related cancer treatment and drug development. Related papers were published online in the internationally renowned academic journal Nature Communication.
Analysis of crystal structure of Paf1 and Ctr9 subcomplexes
In yeast fermentation, plant flowering results, fertilized egg development and human life, the gene expression of cells is in an orderly state in time and space, and responds to changes in environmental conditions in a timely manner. Gene transcription elongation is a highly ordered and extremely complex regulatory process of cell-regulated gene expression, requiring the participation of multiple transcription factors.
In eukaryotes, the highly conserved polymerase II-associated factor 1 complex is abbreviated as the Paf1 complex, which plays an important role in regulating gene transcription elongation and chromatin modification. In addition, the Paf1 complex plays a role in many biological processes such as cell cycle regulation, stem cell pluripotency maintenance, DNA repair and signal transduction. Therefore, the Long Jiafu team focused its research on “analysis†of the Paf1 complex.
"The Paf1 complex consists of five protein subunits, which play an auxiliary role in the transcription of RNA polymerase II and participate in the methylation modification of histones in chromatin." Long Jiafu introduced five protein subunits. Intact complexes function in transcriptional elongation within cells, where any two or more protein subunits are collectively referred to as a subcomplex. Paf1 and Ctr9 are two important protein subunits in the Paf1 complex, and mutations in both can lead to the development of cancer and other related diseases.
After years of painstaking research, the Longjiafu team has comprehensively utilized the multi-disciplinary methods and methods of biochemistry, structural biology and cell biology, and simultaneously analyzed the crystal structure of the human and yeast source Paf1-Ctr9 subcomplex. The study finally found that the Paf1-Ctr9 subcomplex is very important for the assembly of the entire Paf1 complex, revealing the molecular basis of the mutations in the Paf1 and Ctr9 genes, and revealing the histone methylation modification and yeast viability. The important role of the aspect.
Helps screen drug targets and small molecule anticancer drugs
There are about 40,000 genes in the human body, but not every gene has normal functions, and some are so-called defective genes, which often become pathogenic genes. Every healthy person carries 5-6 disease-causing genes, but its pathogenicity is still lurking.
The highly conserved multifunctional Paf1 complex was originally discovered in budding yeast and has been studied for decades. Long Jiafu introduced that at present, there are still some limitations in the world's understanding of the structural information of Paf1 complexes of different species. In the rapid development of cryo-electron microscopy technology, German researchers have obtained structural information of the high-resolution yeast source Paf1 complex, but the resolution is far from the atomic level. In China, researchers at Beijing Normal University have also extended the understanding of the assembly mechanism of the Paf1 complex by analyzing the crystal structure of the Ctr9-Paf1-Cdc73 subcomplex in thermophilic fungi.
Previous studies have reported that abnormal expression or mutation of Ctr9 and Paf1 in genes is likely to cause diseases such as leukemia, pancreatic cancer, ovarian cancer, nephroblastoma and breast cancer. Based on the analysis of the crystal structure of human Paf1-Ctr9, Professor Long Jiafu's team further revealed the possible molecular basis of the disease caused by the mutation of Ctr9 and Paf1 through biochemical and cell biology methods. By disrupting the assembly of the Paf1 complex and then affecting histone modifications (methylation, etc.), it may be involved in regulating the expression of related genes during the development of the disease, eventually leading to disease.
"Analysis of the crystal structure of the Paf1-Ctr9 subcomplex is to understand the fine structure and conformation of these two proteins at the atomic level, and also lays a foundation for the future transformation of the subcomplex. At the same time, the human and yeast sources are analyzed. The structure can further understand the mechanism of action of the Paf1 complex in transcriptional elongation, and clarify that the molecular mechanism of the Paf1 complex from lower eukaryotes such as yeast to higher mammals in humans is quite conserved in transcriptional elongation. Professor Long Jiafu said that the biggest role of this work is to lay a preliminary foundation for the screening of subsequent drug targets and the design and development of anti-cancer small molecule drugs, which is likely to become the gospel of related cancer patients. (Reporter Sun Yusong correspondent Wu Junhui)
Source: Technology Daily
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