April 07, 2026

Scripps Research scientists uncover new mechanism cancer cells use to survive DNA damage Discovery reshapes understanding of how tumor cells repair broken DNA, pointing toward more precise cancer therapies.

April 07, 2026

LA JOLLA, CA A cancer drug target already being investigated in clinical trials turns out to be doing something even more consequential than researchers realized. Scientists at Scripps Research have discovered that the enzyme Pol theta (Pol ) drives a DNA repair mechanism directly at broken replication forks one of the most frequent forms of DNA damage in cancer cells. The findings, published in Molecular Cell on March 16, 2026, help explain how tumors survive relentless replication stress and clarify why Pol theta inhibitors may be an effective strategy to selectively target cancer.

We've uncovered a whole new dimension of how cancer cells cope with DNA damage at replication forks, says Xiaohua Wu, professor at Scripps Research and senior author of the study.

Every time a cell divides, it must make an exact copy of its entire genome, a process carried out by molecular machinery that unzips the DNA double helix and reads each strand to build a new one. The point where this unzipping and copying actively happens is called a replication fork. But when this replication machinery encounters damage, forks can stall or collapse, leaving behind dangerous one-ended DNA breaks that are particularly difficult to repair and, if left unresolved, can kill the cell. This is particularly true in cancer cells, where replication stress is constant.

Scientists previously thought that a repair pathway called break-induced replication (BIR) was the primary first responder to this type of damage. BIR uses an intact DNA template to restart replication, making it relatively accurate but slow. In contrast, microhomology-mediated end joining (MMEJ) is a faster, more error-prone process that repairs breaks by aligning short matching DNA sequences. The prevailing view was that BIR was the active, front-line mechanism, while MMEJ was predominantly used to repair replication-independent double-ended double-strand breaks. But the Scripps Research discovery overturns that view.

Understanding that MMEJ is operating there directly, and through a distinct set of rules, gives us a clearer picture of why tumors are so resilient, and how we might exploit that for treatment.

Because microhomology sequences are frequently found in cancer genomes, Wu and her lab wanted to investigate whether MMEJ also operates to repair broken replication forks. The team combined key emerging technologies to study this process in unprecedented detail: CRISPR nickase technology, to mimic the damage that triggers replication fork collapse in real cells; specialized reporter systems, molecular tools that signal when a specific repair event occurs inside living cells; and genome sequencing, to track the deletion patterns each pathway leaves behind.

What they found surprised them.

When we looked closely at what was happening at these broken forks, we kept seeing mutational signatures that didn't fit the BIR model, explains Shibo Li, first author of the study and former postdoctoral researcher in the Wu lab. That told us something else was going on, and when we started pulling on that thread, we found that MMEJ was there, acting early and directly at the fork.

The finding pointed to Pol theta as the engine driving MMEJ activity right at the moment of fork collapse, before BIR, which has been thought of as the primary mechanism to repair broken forks.

The team also discovered that fork-MMEJ behaves differently from its standard canonical form, which was observed at replication-independent breaks. While both rely on Pol theta, fork-MMEJ is initiated by the protein RPA and produces uneven deletion patterns on either side of the break, a distinctive fingerprint that sets it apart from its canonical form. These error-prone repair signatures are frequently observed in cancer genomes, suggesting the MMEJ mechanism may enable tumor cells to survive otherwise lethal DNA damage.

We expected fork-MMEJ to follow the same rules as the version we'd studied before, says Wu. Finding that it didnt follow the same rules meant that we were looking at something entirely new.

Several Pol theta inhibitor drugs are already in clinical development, with early promise in cancers harboring BRCA1 or BRCA2 mutations. These mutations, linked to hereditary breast and ovarian cancer, disable a major DNA repair pathway that leaves tumor cells unusually dependent on MMEJ for survival. By showing that MMEJ is an active front-line responder at broken forks rather than a backup, the study suggests that blocking Pol theta could be more disruptive to cancer cell survival than previously understood.

The study also identifies a promising combination strategy. The team found that ATR, a cellular protein that senses DNA damage, acts as a pivotal switch at broken forks, suppressing fork-MMEJ while steering cells toward BIR. When the researchers blocked both ATR and Pol theta together, cancer cells under replication stress died at far higher rates, while normal cells were largely unaffected. Because ATR inhibitors are already in clinical development, this synergistic effect points toward a potential combination therapy approach.

This changes how we think about when and why to use Pol theta inhibitors, says Wu. If this pathway is acting at the very moment a fork breaks, not just at replication-independent breaks, then disrupting it could be far more consequential for cancer cells than we realized, as cancer cells are constantly under replication stress that causes replication fork breakage.

The lab's next steps include identifying additional proteins in the fork-MMEJ pathway each representing a potential new drug target and furthe

LINK:	https://www.scripps.edu/news-and-events/press-room/2026/20260407-wu-mo...
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