Rogue DNA Repair Gene EXO1 Creates BRCA-Like Vulnerability in Multiple Cancers

A DNA repair gene that normally safeguards the genome may turn into a molecular saboteur when produced in excess — and that betrayal could open the door to new treatment options for patients whose cancers lack BRCA mutations. Researchers at Penn State College of Medicine (搜索)搜索该词条 have shown that overexpression of the gene EXO1查看药品详情 creates the same therapeutic vulnerabilities seen in BRCA-mutant tumors, potentially expanding the reach of targeted therapies like olaparib查看药品详情 to a far wider range of cancers.

The findings, published February 25, 2026, in Nature Communications, reveal that EXO1查看药品详情 is overproduced in 20% to 30% of breast and ovarian cancers, as well as in melanoma (搜索)搜索该疾病, testicular, cervical, and hepatobiliary cancers that arise in the liver, gallbladder, and bile ducts.

A Double-Edged Molecular Scissor

Under normal conditions, EXO1查看药品详情 functions like molecular scissors that help trim and repair damaged DNA, maintaining genomic stability. But the Penn State team found that when cancer cells produce too much of the protein, those scissors begin cutting DNA structures that should remain intact.

"Regardless of which pathway, EXO1查看药品详情 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double-strand breaks, which we ultimately think is what makes the tumor more sensitive to chemotherapy and increases cell death," said Alexandra Nusawardhana, the lead author of the study who earned her doctorate in biomedical sciences this year from Penn State College of Medicine (搜索)搜索该词条.

The researchers demonstrated that excess EXO1查看药品详情 destabilizes newly formed DNA through two main mechanisms: expanding single-stranded DNA gaps and degrading reversed replication forks. Both processes erode DNA and result in localized loss of genetic material, according to senior author George-Lucian Moldovan, professor of molecular and precision medicine at Penn State.

To confirm that the observed DNA damage stemmed from EXO1查看药品详情's enzymatic activity rather than simply the protein's presence, the team created a disabled version of the gene that produced inactive proteins. Laboratory experiments using commercially available human cancer cells confirmed that the damage required active EXO1.

Mimicking BRCA Mutations Without the Mutation

BRCA proteins normally help protect vulnerable DNA structures during replication. When BRCA genes are mutated, cells lose part of this protective function, increasing cancer risk. The Penn State researchers discovered that excessive EXO1查看药品详情 activity can overwhelm those same protective mechanisms even in cells with fully functional BRCA genes.

"Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells," Moldovan said.

The team also found that EXO1查看药品详情 works alongside a protein called MRE11 to enlarge DNA gaps and generate dangerous DNA breaks. Importantly, unlike BRCA mutations, EXO1 overexpression is not inherited, and researchers do not yet know whether it directly causes cancer.

Therapeutic Sensitivity Confirmed

Because EXO1查看药品详情-overexpressing tumors behaved so similarly to BRCA-mutant cancers, the researchers investigated whether they would also respond to the same treatments. They tested olaparib查看药品详情, a PARP inhibitor commonly used against BRCA-mutant cancers that targets cellular DNA repair pathways. Tumors with elevated EXO1 proved highly sensitive to the drug, responding in a manner similar to BRCA-mutant cancers.

The team also found that EXO1查看药品详情-overexpressing tumors responded to cisplatin查看药品详情, a widely used chemotherapy drug. Their findings raise the possibility that lower doses of cisplatin might achieve comparable tumor shrinkage while reducing side effects.

"EXO1查看药品详情 doesn't predict cancer risk, but it could potentially serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapy treatments, leading to more personalized therapies," Moldovan said. "The same drugs that are reserved for treating BRCA-mutant tumors and that have fewer side effects could potentially be used to treat EXO1 overexpressing tumors, which don't have BRCA mutations. It would expand the applicability of those drugs."

A Step Toward Mutation-Guided Treatment

The researchers analyzed tumor data from The Cancer Genome Atlas, a National Cancer Institute cancer genomics program, confirming elevated EXO1查看药品详情 levels across multiple cancer types. High EXO1 expression was particularly associated with basal-like breast cancer (搜索)搜索该疾病, an aggressive form of the disease.

Because EXO1查看药品详情 overexpression appears in a wider range of tumors than BRCA mutations, Moldovan said it could become a valuable biomarker for guiding treatment decisions. "We shouldn't treat cancers based on what tissue they come from but based on the landscape of the genetic mutations present in the tumors," he said. "That would result in high efficiency treatment. That's the future of cancer treatment."

The research team plans to continue studying EXO1查看药品详情 with the long-term goal of launching clinical trials involving patients whose tumors overexpress the gene. The work was supported by funding from the National Institutes of Health and Four Diamonds. Claudia Nicolae, assistant professor of molecular and precision medicine at Penn State College of Medicine (搜索)搜索该词条, also contributed to the study.