Researchers Uncover Cancer Vulnerability Linked to Misbehaving DNA Repair Gene

Researchers have discovered that a gene normally responsible for repairing damaged DNA may actually contribute to cancer-related changes when it becomes overly active. The study, published in Nature Communications, found that excessive levels of the DNA repair gene EXO1 can destabilize the genome and promote DNA damage instead of preventing it.

Tumor suppressor and DNA repair genes are generally considered protective because they help maintain genetic stability and prevent harmful mutations. However, the new findings suggest that too much EXO1 can become harmful. Researchers analyzed cancer databases and found that EXO1 is overexpressed in roughly 20% to 30% of breast and ovarian cancers, as well as in melanoma, cervical, testicular, and hepatobiliary cancers.

To investigate its effects, scientists increased EXO1 activity in human cancer cells. They discovered that the protein acts like molecular scissors, and when present in excess, it begins cutting DNA structures that should remain intact during replication. This process creates harmful DNA lesions, including double-strand breaks, a severe form of DNA damage linked to cancer development.

The study also revealed that tumors with elevated EXO1 levels behave similarly to cancers carrying BRCA mutations, which are well known for increasing hereditary breast and ovarian cancer risk. Remarkably, these BRCA-like features appeared even when BRCA genes were functioning normally.

Researchers found that EXO1-overexpressing tumors were highly sensitive to olaparib, a targeted therapy commonly used for BRCA-mutant cancers. They also responded to cisplatin, a widely used chemotherapy drug. These findings suggest that EXO1 could serve as a biomarker to help identify patients who may benefit from DNA repair-targeted treatments despite lacking BRCA mutations.

Researchers hope future clinical studies will determine whether testing for EXO1 levels can help guide more personalized cancer treatment strategies.

REFERENCE: Alexandra Nusawardhana, Claudia M. Nicolae, George-Lucian Moldovan. The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells. Nature Communications, 2026; 17 (1) DOI: 10.1038/s41467-026-69981-1