肿瘤基因 z-bo 2020-12-16 383

　　Compared with normal cells, cancer cells divide very quickly. Such a "crude" product has a fairly stable genome "quality"-how do they do it? The team of Professor Hickson of the University of Copenhagen, Denmark, and the team of Professor Shen Huahao, the Second Affiliated Hospital of Zhejiang University School of Medicine-Zhejiang University Respiratory Diseases Institute, discovered for the first time that tumor cells have DNA replication behavior during mitosis, which is the key to tumor cells maintaining genome stability .

　　The classic cell division theory tells us that a complete cell division cycle is divided into the pre-replication phase (G1), the DNA replication phase (S), the late replication phase (G2) and the mitotic phase (M). Academia generally believes that DNA replication can only occur in the S phase of the cell cycle.

　　 "We found this interesting phenomenon outside of the classical theory on tumor cells." said co-first author and professor Ying Songmin of Zhejiang University School of Medicine. Normal cell division follows the classic cell division cycle theory, and DNA replication is completed in S phase. "This is like a worker who works hard for 8 hours and produces products of high quality. However, tumor cells have another set of mechanisms. They quickly perform DNA replication in the S phase of the'prescribed action', which would otherwise take 8 hours to complete. The work is finished in 6 hours. This will inevitably "cut corners" and leave a lot of DNA damage, which makes the DNA very unstable, and they are more likely to be injured than normal cells." The study found for the first time that the mitotic phase, cancer Cells also have DNA replication behavior. "The tumor cells are too rough during the day, and there are many leftovers, so they can only work overtime at night."

　　 Ying Songmin said: "We also discovered that DNA replication in the mitotic stage is unique to tumor cells and is particularly important for maintaining the stability of tumor cell genes."

　　 Professor Ian Hickson, academician of the Royal Society, pointed out that the discovery of DNA replication during mitosis will have an important impact on research in many fields, including nucleic acid repair, replication and cancer research. Professor Liu Ying from the University of Copenhagen in Denmark pointed out that the importance of this research is to solve a long-standing unresolved scientific problem in this field. Professor Shen Huahao, one of the co-corresponding authors and Zhejiang University School of Medicine, pointed out that the incidence of lung cancer and other malignant tumors has been increasing in recent years. The signal pathways specifically dependent on tumor cells discovered in this study provide a new way for future tumor targeted therapies. Potential therapeutic target. "If we can find a way to stop the DNA replication of tumor cells during mitosis, we can control the proliferation of tumor cells by weakening the stability of tumor cell DNA."

　　 It is reported that based on the results of this research, the Institute of Respiratory Diseases of Zhejiang University is currently conducting multiple research projects to further study the molecular mechanism of DNA damage repair and its pathological regulation of chronic airway inflammation and lung cancer. This research was supported by the Outstanding Youth Science Foundation (81422031), Zhejiang Outstanding Youth Science Foundation (LR14H160001) and the National Clinical Research Center Project (2013BAI09B09).

　　 Researchers from the University of Copenhagen, Denmark, and Zhejiang University School of Medicine have discovered that replication stress during mitosis can activate DNA synthesis at common fragile sites. This important research finding was published in the December 2 issue of Nature.

　　Huahao Shen, Associate Dean of Zhejiang University School of Medicine and Distinguished Professor of "Yangtze River Scholar", and Professor Ian D. Hickson and Associate Professor Ying Liu of the University of Copenhagen are the co-corresponding authors of this paper. In the cell growth and reproduction cycle, DNA replication is the central law of heredity. The correct progress of the DNA replication process is the key to ensuring the stable delivery of genetic material. Any error in the DNA replication process may lead to mutation or deletion of genetic material, induce or promote tumors. occur. The DNA replication pressure induced by oncogene activation tends to cause chromosomal fragile sites to break, which is an important driving factor for tumor formation.

　　 Fragile sites refer to the site-specific regions where chromosomes are prone to gaps or breaks in the early stages of mitosis (extended reading: PNAS: Map the "fragile sites" of the whole genome). Usually fragile sites are stable in somatic cells, but they are often deleted or rearranged in many cancer cells and certain neurological disease cells, indicating that their instability is closely related to the pathogenesis of these diseases.

　　 Fragile sites can be divided into two types: common type (CFSs) and rare type. Common fragile sites can appear in all individuals and are a basic feature of chromosomes, while rare fragile sites only appear in less than 5% of the population. CFSs are sites that are difficult to replicate. When cells are under replication pressure, they appear as gaps or breaks on metaphase chromosomes (called CFS ‘expression’). MUS81–EME1 structure-specific endonucleases promoted the appearance of chromosomal gaps or breaks in CFSs after replication stress.

　　 In this Nature article, the researchers confirmed that the cell's entry into the pre-mitotic phase triggered the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 can promote POLD3-dependent DNA synthesis at the CFSs site, thereby inhibiting chromosomal erroneous segregation and non-segregation. Researchers believe that the attempt to condense the incomplete replication site in the early mitosis triggered the end of DNA replication at the CFS site in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells showing high levels of chromosomal instability (CIN+) and replication pressure, this POLD3-dependent signaling pathway is used to counter the high level of replication pressure . As a result, the researchers proposed that targeting this signaling pathway may be a new potential anti-cancer treatment strategy.