Most cancers-fighting gene restrains ‘leaping genes’

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Cancer-fighting gene restrains 'jumping genes'

This figure shows how retrotransposons are "handcuffed" by the tumor suppressor gene p53. However, if p53 is lost, these mobile elements can break out. Photo credit: Study authors, Amanda Jones and Bhavana Tiwari. Artwork by Angela Diehl.

About half of all tumors have mutations in the p53 gene, which is normally responsible for the defense against cancer. Now scientists at UT Southwestern have discovered a new role for p53 in the fight against tumors: They prevent retrotransposons or "jumping genes" from hopping around the human genome. In cells with missing or mutated p53, retrotransposons moved and reproduced more than usual. The finding could lead to new ways of detecting or treating cancers with p53 mutations.

"There is a longstanding literature linking retrotransposons to cancer," said John Abrams, Ph.D., professor of cell biology at UTSW and lead author of the study recently published in Genes & Development. "This work provides the first empirical connection between p53 and retrotransposons in humans."

The role of p53 as an anti-cancer or tumor suppressor gene is well known. It blocks cell growth or induces cellular suicide when the cells are under stress or divide abnormally, as is the case with tumors. However, researchers have long wondered whether the gene has any other function. Even if p53's previously known targets – genes involved in cell growth and death – are removed or mutated, p53 still protects cells from cancer, suggesting additional, unknown targets. In addition, the gene occurs throughout evolution, including in ancient unicellular organisms.

"These genes existed long before the need to block cancer," says Abrams. "My laboratory wondered what originally drove the evolution of p53 genes and whether this knowledge could help us fight cancer."

Retrotransposons are sections of DNA that can be inserted into new locations in the genome after being transcribed into RNA. These mobile genetic elements are seen as beneficial to some extent – they can help genes develop with new functions. However, they also have the potential to mix genomes and insert themselves into genes that are critical to cell health and growth, and potentially contribute to cancer.

In 2016, Abrams and his colleagues discovered that retrotransposons were particularly mobile when p53 was inactivated in cells of flies and fish. In the new work they wanted to investigate whether this is also the case in human cells.

When the researchers used CRISPR-Cas9 gene editing technology to remove p53 from human cells, they found that the incidence of retrotransposons increased rapidly. Cells derived from both cancer and normal lung tissue and engineered to lack p53 had about four times the speed of retrotransposon movement than cells still containing p53.

Abrams' team also introduced a synthetic, fluorescently labeled retrotransposon into cells that allowed them to follow the movement of the retrotransposon throughout the genome in real time. The results were similar to their first experiment; The retrotransposon was about four times more mobile and therefore became more common over time when the cells were lacking p53. The finding suggests that one way p53 prevents cancer is by preventing retrotransposons from leading to other cancer-causing mutations.

"In the clinic, this information could be used to detect or mitigate potentially p53-related cancers by quantifying or blocking retrotransposon activity," says Abrams. For example, a fluid biopsy could be developed to detect an overabundance of retrotransposons, which theoretically precede cancer or are easier to detect than other cancer mutations.

The research team further solidified the link between p53 and retrotransposons by showing that the p53 protein binds directly to a region of human retrotransposons. And they showed that a drug that blocks the ability of retrotransposons to copy themselves prevents inflammation that otherwise occurs in cells with high retrotransposon movement. More work is needed to determine whether an anti-retrotransposon drug can slow or stop the growth of existing cancers.

"Jumping sequences" can change gene expression in melons

More information:
Bhavana Tiwari et al. p53 directly suppresses human LINE1 transposons, Gene & Development (2020). DOI: 10.1101 / gad.343186.120

Provided by
UT Southwestern Medical Center

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