Researchers at Penn State College of Medicine report that unusually high activity of the DNA-repair gene EXO1 can damage newly replicated DNA and create BRCA-like weaknesses in some tumors, potentially helping identify patients who could respond to certain treatments used for BRCA-mutant cancers.
Scientists at Penn State College of Medicine say a gene best known for helping fix DNA can become harmful when produced in excess.
In a study published in Nature Communications, the team reports that the DNA nuclease EXO1—an enzyme that normally helps process damaged DNA—can destabilize the genome when overexpressed, producing DNA damage patterns that resemble those seen in BRCA-deficient cells even when BRCA genes are intact.
Analyzing cancer datasets, the researchers found evidence that EXO1 is overexpressed in roughly 20% to 30% of breast and ovarian cancers, and that EXO1 alterations also appear in other tumor types including hepatobiliary cancers, melanoma, testicular cancers, and cervical cancer.
Lab experiments in human cancer cell lines suggested that excess EXO1 can undermine newly formed DNA through two main mechanisms—expanding single-stranded DNA gaps and degrading reversed replication forks—leading to the accumulation of toxic DNA lesions, including double-strand breaks.
“EXO1 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,” said George-Lucian Moldovan, a professor of molecular and precision medicine and the study’s senior author.
The study also links EXO1-driven DNA damage to heightened drug sensitivity. The researchers report that tumors with elevated EXO1 showed strong sensitivity in testing to olaparib, a PARP inhibitor widely used in certain BRCA-mutant cancers, and also responded to the chemotherapy drug cisplatin.
The team said further work is planned with the long-term aim of moving toward clinical trials for patients whose tumors overexpress EXO1.
The research was supported by funding from the National Institutes of Health and Four Diamonds, according to the Penn State release.
