Cancer’s super-enhancers may set the map for DNA breaks and repair: A key clue to why tumors become aggressive and genetically unstable

(Press-News.org) New study shows that cancer damages its own DNA by pushing key genes to work too hard. Researchers found that the most powerful genetic “on switches” in cancer cells, called super-enhancers, drive unusually intense gene activity. That high gear creates stress on the DNA and can cause dangerous breaks. Cancer cells can often repair this damage, but the process is frequently error-prone, the repeated cycle of breaking and repairing can make these regions more prone to accumulating mutations over time. In short, the same mechanisms that help cancer grow quickly may also make its DNA more fragile, helping explain how tumors continue to evolve and, in some cases, become more aggressive over time.

 

Cancer cells grow by turning certain genes on at extremely high levels, especially genes that help them multiply. But a new study suggests that this frantic activity comes with a cost: it can physically damage the cell’s DNA.

The research, published in Science Advances, was led by PhD student Osama Hidmi under the guidance of Prof. Rami Aqeilan of the Hebrew University of Jerusalem and reveals an overlooked source of genetic instability in cancer. The team found that DNA breaks in cancer cells often occur in the same places where the disease is pushing growth genes the hardest. The focus was on super-enhancers, stretches of DNA that act like powerful control panels, boosting the activity of nearby genes and keeping cancer-driving programs running at full volume.

Using a sensitive genome-mapping approach, the researchers generated detailed maps of double-strand breaks, one of the most serious kinds of DNA damage, in which both strands of the DNA molecule snap. The breaks were not random: they cluster within genes driven by super-enhancers, suggesting that when cancer forces certain genes to run nonstop, it can strain the system enough to trigger breaks.

The team also tracked a natural “alarm” signal cells use to flag DNA damage and bring in repair crews. They found that cancer cells repeatedly break and repair DNA in these high-activity regions. While this helps tumors survive, frequent repair can raise the chance of small mistakes, making these sites more likely to accumulate new mutations over time.

“Cancer cells rely on super-enhancers to keep growth genes running at high speed,” said Prof. Rami Aqeilan. “What we found is that this same high-output activity can put real strain on the DNA, creating break hotspots that the cell has to repair again and again. That cycle may help tumors survive in the short term, but it also increases the risk of mutations that can fuel cancer’s evolution.”

“What is especially exciting,” added Osama Hidmi, the PhD student who led the study, “Because cancer cells depend on these high-stress DNA regions to keep growing, they may also be more vulnerable there. This opens the door to treatments that target the very processes tumors rely on to survive.”

Why this matters

DNA damage and repair are central to how cancers grow, change, and resist treatment. This study helps explain where some of the most important damage happens and why. By showing that cancer’s strongest gene-control regions are also sites of repeated DNA stress, the research points to potential weak spots in tumors, areas that may be especially sensitive to treatments that disrupt runaway gene activity or interfere with DNA repair. Understanding this process could help researchers design strategies that make it harder for cancer to adapt and evolve.

By revealing how cancer’s drive to grow can destabilize its own DNA, the study adds an important piece to the puzzle of why tumors are both aggressive and genetically unstable, and how that instability might eventually be used against them.

 

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