Overactive DNA repair gene can damage DNA and reveal cancer vulnerability
Penn State College of Medicine researchers found that excessive activity of the EXO1 gene damages DNA, mimicking BRCA mutations, and could serve as a biomarker for targeted therapies.
Tumor suppressor genes are typically seen as the body's defense against cancer, but new research shows that too much of one DNA repair protein can be harmful. Scientists at Penn State College of Medicine discovered that overexpression of the EXO1 gene damages DNA instead of repairing it, destabilizing the genome—a hallmark of cancer. The study was published in Nature Communications.
EXO1 overexpression was found in 20–30% of breast and ovarian cancers, as well as melanoma, testicular, cervical, and hepatobiliary cancers. Remarkably, cells with elevated EXO1 behaved similarly to cells carrying BRCA mutations, even when BRCA genes were normal. 'EXO1 doesn't predict cancer risk, but it could serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapies,' said senior author George-Lucian Moldovan.
In lab experiments, artificially increasing EXO1 production in human cancer cells showed that the excess protein acts like molecular scissors, cutting intact DNA structures. It destabilizes newly formed DNA by expanding single-stranded gaps and degrading reversed replication forks. 'Regardless of the pathway, EXO1 overexpression leads to toxic DNA lesions that increase chemotherapy sensitivity,' noted lead author Alexandra Nusawardhana.
Tumors overexpressing EXO1 were highly sensitive to olaparib, a drug used against BRCA-mutant cancers, and also responded to cisplatin. This suggests that patients without BRCA mutations but with high EXO1 levels could benefit from these drugs. 'We should treat cancers based on the genetic mutations in the tumor, not the tissue of origin,' Moldovan said. The team plans further research toward clinical trials.
