The synthetase in the human body has both “good and evil sides”. If it is in the cytoplasm, it usually does good deeds, which can resist infection and activate immune response. Once it escapes from the cytoplasm into the nucleus, it starts to do evil, which inhibits the DNA repair of cells, so as to promote tumor development. This important discovery of the research team of Ge Baoxue, Professor of Tongji University School of Medicine and Pulmonary Hospital Affiliated to Tongji University, and Mao Zhiyong, Professor of Life Science and Technology College of Tongji University and The first maternity and infant health care hospital Affiliated to Tongji University, was published online on October 25th in Nature, the international top academic journal. It was the first time to systematically explain the new functions of cGAS in the nucleus which was completely independent of DNA recognition function, thus providing a theoretical basis for the development of new anti-tumor drugs based on the intervention of cGAS into nucleus.

Early this morning, Nature magazine sent an email to the research team, saying that the paper would also be reported as a highlight by the internationally famous academic journal Nature Reviews Molecular Cell Biology.

cGAS, known as cyclic GMP-AMP Synthase, was a DNA recognition receptor. It was first identified by Prof. Chen Zhijian, a famous Chinese scholar in the United States. It was a milestone in the field of DNA recognition and innate immunity. The synthetase could promote the production of type I interferon and immune factors.

In the process of normal growth and metabolism in cells, DNA is always damaged in different forms due to various internal and external factors. DNA double strand break is one of the most serious forms of DNA damage. If it can not be repaired or be wrongly repaired, it will lead to the increase of genomic instability, and then induce the rearrangement of chromosomes and the loss of genetic information, which will eventually lead to apoptosis, cell senescence and even the occurrence of tumors.

cGAS entered nucleus.

According to the cooperative research of researchers, when DNA damage occured in cells, cGAS could transfer into the nucleus and be recruited to the site of DNA damage. By interfering with the formation of PAPR1/Timeless complex, cGAS could inhibit the repair of DNA double strand break damage, thus increasing the instability of genome and ultimately increasing the risk of tumor formation. It was also found that the inhibition of cGAS on DNA repair was a pathway completely independent of its DNA recognition function.

cGAS was recruited to the site of DNA damage .

"cGAS can inhibit DNA repair and promote tumor formation, which is the first time that we have found a new function of cGAS in the world." Prof. Ge Baoxue introduced that in the past, the understanding of cGAS was focused on innate immunity, that was, as a DNA receptor, cGAS could recognize the external pathogenic microorganisms and the self DNA in the human cytoplasm, and activated the immune response. The research on its physiological process was only in the cytoplasm. However, this cancer promoting function of cGAS, was found for the first time, so this achievement would push the functional research of cGAS to a new field.

cGAS affected genome stability.

This important discovery laid a theoretical foundation for the development of new anti-tumor drugs. "cGAS is like a devil locked in a bottle," said Prof. Ge Baoxue. "Entering the nucleus" was a key point. If we could intervene cGAS and keep it "locked" in the cytoplasm, it would not break into the "nucleus" to do bad things. This would become an important target in the development of anti-tumor drugs.

Pattern diagram

"To do research, we need to broaden our thinking and vision. There are two aspects of things: Yin and Yang. We hope that our findings can provide some research ideas and innovative inspiration for researchers." Said Prof. Ge Baoxue.

Prof. Ge Baoxue and Prof. Mao Zhiyong were the co-corresponding authors of this paper. Liu Haipeng, associate researcher of Shanghai Pulmonary Hospital affiliated to Tongji University, Zhang Haiping, Ph.D. student of Tongji University School of Life Science and Technology, and Wu Xiangyang, Ph.D. student of Tongji University School of Medicine were the co-first authors. The research work was supported by the Ministry of science and technology, the National Natural Science Foundation of China and the Shanghai Municipal Science and Technology Commission, and supported by research teams such as Fudan University, Xiangya Medical College and Max Planck Institute of Infectious Biology in Germany.

In recent years, Prof. Ge Baoxue's team has carried out research in the field of innate immune signal molecular functional mechanism and translational medicine, and has successively published a series of important research results in multiple subjournals of Nature, such as Nature Immunology, Nature Communications and so on. In the future, based on these basic research results, the team will work with the clinic to carry out translational medicine research and serve for the treatment of major clinical diseases.