抗癌基因 z-bo 2020-11-02 327

　　About half of all tumors have mutations in the gene p53, which is usually responsible for fighting cancer. Now, scientists at UT Southwestern University have discovered a new role of p53 in fighting tumors: preventing retrotransposons or "jumping genes" from jumping in the human genome. The research team found that in cells with p53 deletion or mutation, retrotransposon movement and expansion are more common than usual. This discovery may lead to new methods of detecting or treating cancers with p53 mutations.

　　Dr. John Abrams, professor of cell biology at UTSW and the senior author of the study, said: “There have been many documents linking retrotransposons with cancer. What this work has done is to establish the first link between p53 and retrotransposons in humans. An empirical connection."

　　The role of p53 as an anti-cancer or tumor suppressor gene has been recognized. When cells are under stress or divide abnormally, it works by preventing cell growth or inducing cell suicide, just like in tumors. But researchers have always wanted to know whether the gene has other functions. Even if the previously known p53 targets (genes involved in cell growth and death) are removed or mutated, p53 can still protect cells from cancer, indicating the existence of other unknown targets.

　　Abrams said: "These genes existed long before the need to block cancer. My lab wanted to know what drove the evolution of the p53 gene in the first place, and whether this knowledge could help us target cancer."

　　A retrotransposon is a piece of DNA that can insert itself into a new site in the genome after being transcribed into RNA. These fluid genetic elements are considered to be beneficial to some extent, and they can help genes evolve new functions. However, they may also shuffle the genome and insert it into genes essential for cell health and growth, which may lead to cancer.

　　In 2016, Abrams and his colleagues discovered that retrotransposons are particularly mobile when p53 is inactivated in fruit flies and fish cells. In this new work, they set out to investigate whether the same is true in human cells.

　　When researchers used CRISPR-Cas9 gene editing technology to remove p53 from human cells, they found that the number of retrotransposons increased rapidly. Cells derived from cancer and normal lung tissues engineered to lack p53 have a retrotransposon movement rate approximately four times that of cells still containing p53.

　　Abrams’ team also introduced synthetic retrotransposons with fluorescent tags to cells, enabling them to track the movement of retrotransposons throughout the genome in real time. The results were similar to their first experiment; the mobility of retrotransposons was increased by about four-fold, so when cells lack p53, retrotransposons became more common over time. This finding suggests that one way p53 can prevent cancer is to prevent retrotransposons from causing other cancer-causing mutations.

　　Abrams said: "In the clinic, people can use this information to detect or reduce p53-driven cancers by quantifying or blocking the activity of retrotransposons." For example, liquid biopsy can be performed to detect retrotransposons. In theory, the abundance of it may precede the cancer or be more easily detected than other cancers.

　　The research team further consolidated the connection between p53 and retrotransposons by proving that p53 protein directly binds to a region of human retrotransposons. They found that drugs that block the ability of retrotransposons to replicate themselves can prevent inflammation that would otherwise be seen in cells with high levels of retrotransposon movement. More work is needed to determine whether drugs targeting retrotransposons can slow or prevent the growth of existing cancers.