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In a new Science Advances paper, a Hebrew University team maps where tumors break their own DNA and finds the damage clusters at super enhancers, the control panels that keep growth genes switched on.
Cancer's growth switches are physically breaking the tumor's own DNA at the very spots they activate, and the error-prone repairs may be what lets tumors evolve. That is the picture emerging from a new study in Science Advances led by PhD student Osama Hidmi in Prof. Rami Aqeilan's lab at the Hebrew University of Jerusalem.
The work maps where DNA breaks occur across the cancer genome and finds the damage clusters at super-enhancers, the DNA control panels that keep growth genes switched on at full blast. The very intensity of transcription that drives aggressive tumor growth is what physically snaps the DNA in those same regions, the researchers argue. The institutional announcement adds that the breaks line up with the locations where cancer cells are most aggressively driving growth-related genes. Cancer cells patch the breaks, but the repair process is often error-prone, so mutations accumulate right where the growth switches live.
The finding is the first detailed link between growth-gene control regions and physical DNA damage in tumors, according to the Lautenberg Center's write-up. It points to a long-standing puzzle in cancer biology: tumor genomes are unusually unstable around the very genes that drive aggressive growth, and no one has had a clean mechanism to explain why.
Super-enhancers are clusters of regulatory DNA that pin growth-promoting genes in the "on" position. In cancer cells, they run hotter than in healthy tissue, producing huge volumes of RNA from genes that push the cell to divide. The Aqeilan team's mapping approach, a sensitive method for locating DNA breaks across the genome, shows that the breaks occur at those same high-output sites.
The proposed explanation is mechanical. As RNA polymerase and its associated machinery push through these regions at high speed, the DNA is more likely to snap, especially at sequences that already form unusual structures. The breaks are then repaired by the cell's normal machinery, but the DNA damage response at super-enhancers tends to be sloppier than at average sites, and the resulting errors land exactly where growth-driving genes sit.
The team's broader claim is that this is a loop, not a one-off accident. Each cycle of intense transcription, break, and error-prone repair leaves a small mark on the genome. Over time, those marks accumulate at super-enhancers, potentially making the tumor more aggressive, more adaptable, and harder to treat.
For decades, cancer genomics has documented that tumor genomes are chaotic. The new paper offers a specific reason the chaos concentrates at growth genes rather than scattering randomly across the chromosome.
That has two practical implications. First, it gives drug hunters a sharper target: any compound that stabilizes the DNA at super-enhancers, or that blocks the error-prone repair pathway, could in principle slow the mutation engine. Second, it gives diagnosticians a new place to look: if break patterns at super-enhancers predict how a tumor will evolve, sequencing strategies could be designed to track that.
Both ideas are hypothetical. The work is preclinical, the study is a single paper, and the mechanism is one contributor to tumor genomic instability rather than the whole story. There is no clinical trial, no compound in development, and no test yet.
The mapping method is sensitive, but the cancer cells profiled are a limited set, and the paper does not yet show that the same break pattern holds across tumor types. Other mechanisms of genomic instability, including defective DNA repair genes and exposure-driven mutagenesis, are well established and are not displaced by this finding. The error-prone repair step is inferred from the break and mutation patterns rather than directly observed in living tumors.
The Aqeilan lab is positioned to test whether the same super-enhancer break pattern shows up in patient tumor samples and in different cancer types. If it does, the next step would be screens for compounds that specifically reduce breaks at super-enhancers without broadly destabilizing the genome. That is years of work, not a near-term therapy.
For now, the contribution is mechanistic: it pins a long-observed pattern of tumor genomic instability to a specific, mappable cause, and gives the field a new place to aim.