Researchers at ETH Zurich in Switzerland have unravelled the complex network that cells use to repair their genetic material. In examining thousands upon thousands of genetic interactions, the research team discovered new vulnerabilities in cancer cells that could be exploited therapeutically in the future.
The DNA of human cells consists of a sequence of around 3.1 billion building blocks. Cells seek to maintain the integrity of this vast store of information. As such, cells constantly untangle knots in the DNA strand and create new chemical bonds when a strand of DNA breaks somewhere in the nucleus.
According to Jacob Corn, Professor of Genome Biology: “When people read about repairing genetic material, they often think of it being in response to exposure to toxins or radiation”.
However, repair mechanisms not only defend against external threats; they also play a crucial role in helping cells survive the challenges they face in their daily fight for survival.
Wealth of new interactions
Scientists have long known that more than 500 genes (out of approximately 20,000 human protein-coding genes) are crucial for DNA repair. By comprehensively analysing the interactions of these genes, Corn and his team have gained important new insights into how cells maintain the integrity of their genome. The researchers have discovered a wealth of new interactions and have identified potential new targets for cancer therapy.
Here, the researchers modified human cells in culture to switch off two of the repair genes simultaneously. “We took a systematic approach and looked at all possible combinations,” says Corn. This required an extensive exercise as the researchers looked at nearly 150,000 different combinations of inactivations.
“Human cells love redundancy”
Inactivating a single gene is usually not enough to produce a noticeable effect because another gene often compensates for the missing function. “Human cells love redundancy,” says Corn. Only when the backup is also switched off do they lose the ability to repair the genetic material. Sooner or later, the damage accumulates to a point where survival is no longer possible.
This was the case for about 5,000 inactivated gene pairs. In their paper, the researchers provide a detailed description of the molecular interactions lost for two specific gene pairs. In their investigations, they uncovered previously unknown links that appear to be essential for the cell’s survival.
New clues for cancer therapy
The researchers’ work offers important insights and it provides new possibilities for cancer therapy. Cancer cells have more mutations than normal cells. For this reason, some of the 500 repair genes are already switched off in some cancer cells.
Through the research, the team lists a number of previously unknown links between common cancer mutations and molecular targets that can be blocked with drugs.
According to Corn: “These newly discovered potential vulnerabilities in cancer cells now need to be tested. We have shown the pathways through the dark forest. Now it’s easy to walk those paths.”
The research appears in the journal Nature, titled “Comprehensive Interrogation of Synthetic Lethality in the DNA Damage Response”.
