Cancer cells depend on a dangerous DNA repair trick
Researchers have discovered how cells activate a last-resort DNA repair system when severe damage strikes. When genetic tangles overwhelm normal repair pathways, cells flip on a fast but error-prone emergency fix that helps them survive. Some cancer cells rely heavily on this backup system, even though it makes their DNA more unstable. Blocking this process could expose a powerful new way to target tumors.
The DNA inside our cells is under constant attack. One of the most dangerous forms of damage is a double-strand break, which happens when both strands of the DNA helix are cut at the same time. Under normal conditions, healthy cells rely on highly accurate repair systems to fix this kind of damage. When those precise systems break down, however, cells may fall back on a less reliable emergency option. Researchers at Scripps Research have now identified when and how this backup repair process is triggered, and why some cancer cells depend on it to stay alive.
Their findings also suggest that this survival strategy could be turned against tumors that rely on it.
RNA DNA Tangles That Threaten Genome Stability
The study, published in Cell Reports, examined a protein involved in untangling twisted genetic material. This includes structures known as R-loops, which are RNA-DNA tangles that can disrupt normal DNA function. These structures form when newly produced RNA fails to separate from the DNA strand it was copied from, leaving one side of the DNA exposed and vulnerable.
"R-loops are important for many different cell functions, but they must be tightly controlled," says senior author Xiaohua Wu, a professor at Scripps Research. "If they aren't properly regulated, they can accumulate to harmful levels and cause genome instability."
The Role of SETX in Cancer and Neurological Disease
The researchers focused on a helicase protein, part of a group of molecular motors that unwind tangled genetic material, known as senataxin (SETX). Changes in the SETX gene are already linked to rare neurological disorders, including ataxia and a form of amyotrophic lateral sclerosis (ALS). The same mutations also appear in certain uterine, skin and breast cancers. This connection raised an important question. How do cancer cells cope with the stress caused by excessive R-loops when SETX is missing or defective?
A Cellular Crisis Triggers Emergency Repair
To find answers, Wu's team studied cells lacking SETX that showed unusually high levels of R-loops. They then observed what happened when double-strand breaks formed at these tangled sites. As expected, the cells accumulated significant DNA damage. What surprised the researchers was how aggressively the cells responded.
"We were surprised but excited to find that the cell turns on an emergency DNA repair mechanism called break-induced replication (BIR)," says Wu.
Break-Induced Replication as a Backup System
Under normal circumstances, BIR helps rescue stalled DNA replication forks. It can also act as a fallback repair option for double-strand breaks. Instead of making small, precise fixes, BIR copies long stretches of DNA to reconnect broken pieces. This rapid and extensive copying allows cells to survive severe damage, but it comes at a cost.