Scientists find cancer weak spot in backup DNA repair system New findings from Scripps Research reveal how certain tumors survive DNA damage and point to a strategy for targeting them.
December 03, 2025
LA JOLLA, CA The DNA inside our cells is constantly being damaged, and one of the worst kinds of damage is a double-strand break when both sides of the DNA helix are cut at once. Healthy cells can normally fix these breaks using highly precise repair systems, but when those systems fail, cells sometimes resort to a less accurate backup method. Now, scientists at Scripps Research have discovered when and how this backup repair pathway gets activated, and how the process could be turned against cancer cells that rely on it to survive.
The study, published in Cell Reports on October 28, 2025, focused on a protein that unwinds twisted strands of genetic material, including RNA-DNA tangles called R-loops. These temporary, harmful knots form when newly made RNA sticks to its DNA template instead of detaching, leaving one DNA strand exposed.
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 study zeroed in on a type of helicase protein a class of molecular motors that unwind genetic tangles called senataxin (SETX). SETX mutations are known for their role in rare neurological disorders, including ataxia and a form of amyotrophic lateral sclerosis (ALS). SETX mutations are also found in some types of uterine, skin and breast cancers. This raises the question of how tumor cells manage to survive the stress caused by excessive R-loops.
To investigate, Wu's team used SETX-deficient cells with high levels of R-loops and tracked how they responded when double-strand breaks occurred at the sites of R-loops. As expected, these cells showed a surge in DNA damage, but they also switched into a frantic repair overdrive.
We were surprised but excited to find that the cell turns on an emergency DNA repair mechanism called break-induced replication (BIR), says Wu.
This BIR mechanism normally rescues damaged DNA forks during replication, but it can also act as a backup system for double-strand breaks. The process involves proteins that rapidly copy large sections of DNA to patch up broken strands unlike the smaller, more precise fixes of the usual repair pathway. But because BIR copies the DNA so extensively and quickly, it often introduces errors.
It's like an emergency repair team that works intensively but makes more mistakes, says Wu.
The researchers found that when SETX is missing, R-loops build up at the break sites, scrambling the cell's normal repair signals. The broken DNA ends are trimmed too far, exposing long stretches of single-stranded DNA, which in turn attracts the BIR machinery including PIF1, an essential helicase for the BIR process. The combination of exposed DNA strands and PIF1 kick-starts BIR for damage repair.
Despite its error-prone nature, BIR can keep SETX-deficient cells alive, but it also creates a critical weakness. The cells become dependent on BIR for survival, meaning that if BIR is blocked, the cells have no way to repair the breaks, and they die. This concept, known as synthetic lethality, is the basis of several modern targeted cancer therapies.
Wu's team found that SETX-deficient cells rely heavily on three BIR-related proteins: PIF1, RAD52 and XPF.
What's important is that these aren't essential in normal cells, which means we could selectively kill SETX-deficient tumors, says Wu.
The findings are promising, but Wu notes that translating them into treatment will take time.
We're now exploring ways to inhibit these BIR factors, trying to find ones with the right activity and low toxicity, she adds.
Her lab is also studying which types of tumors accumulate the highest levels of R-loops and under what conditions. Identifying the best cancer candidates for BIR-targeted therapy will be an important next step.
Although SETX deficiency isn't the most common cancer mutation, many tumors accumulate R-loops through other mechanisms, such as oncogene activation or hormone signaling like estrogen in certain breast cancers. That means the therapeutic opportunities could apply to a broader set of cancers, not just those with SETX mutations.
In addition to Wu, authors of the study Break-induced replication is activated to repair R-loop-associated double-strand breaks in SETX-deficient cells include Tong Wu, Youhang Li, Yuqin Zhao and Sameer Bikram Shah of Scripps Research; and Linda Z. Shi of the University of California San Diego.
This work was supported by the National Institutes of Health (grants GM141868, CA294646, CA244912 and CA187052).
Cancer Molecular and Cellular Biology Wu, Xiaohua
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Scientists find cancer weak spot in backup DNA repair system New findings from Scripps Research reveal how certain tumors survive DNA damage and point to a strategy for targeting them.
