DNA damage and the failure to adequately repair that damage play a significant role in the development of cancer. For this reason, scientists have long regarded DNA repair mechanisms as systems that protect cells. However, a new study has shown that in some cases, the overactivity of genes involved in DNA repair can also be harmful to cells. The researchers found that when the EXO1 gene—which normally protects DNA—becomes uncontrollably active, it can increase genomic instability and lead to significant changes in cancer cells.
In a study conducted by researchers at Penn State College of Medicine in the U.S. and published in the journal Nature Communications, it was determined that the EXO1 gene is expressed at high levels in many types of cancer. Analyses revealed that EXO1 overexpression is observed in approximately 20 to 30 percent of breast and ovarian cancers. Similarly, high levels of EXO1 were detected in melanoma, testicular, cervical, and hepatobiliary cancers.
How Does the DNA Repair Gene EXO1 Cause Damage in Cancer Cells?
Under normal conditions, EXO1 encodes a protein involved in processing damaged regions of DNA. Because this protein plays a role in DNA repair processes, researchers often refer to it as “molecular scissors.” This mechanism, which is essential for cells, helps maintain genomic integrity when it operates within certain limits.
However, laboratory experiments conducted by the research team showed that this mechanism can spiral out of control when EXO1 levels rise excessively. It was observed that increasing EXO1 production in human cancer cells caused the protein to begin breaking down not only damaged regions but also healthy DNA structures. The researchers also found that EXO1 enlarges single-strand gaps in DNA and causes the disruption of critical structures formed during replication. This process ultimately leads to the accumulation of damage that is extremely dangerous to the cell, such as double-strand DNA breaks.
Prof. Dr. George-Lucian Moldovan, one of the study’s senior researchers, notes that excessive EXO1 activity causes toxic damage to DNA and significantly alters the biology of cancer cells. The researchers also revealed that EXO1 works in conjunction with MRE11—another protein associated with DNA damage—to amplify these effects.
New Hope for Cancer Treatment in Patients Without BRCA Mutations
One of the study’s most striking findings was that tumors with high EXO1 levels exhibit behavior similar to BRCA-mutated cancers. The BRCA1 and BRCA2 genes are among the most important tumor suppressor genes that protect DNA. Hereditary mutations in these genes increase the risk of breast and ovarian cancer in particular. However, the researchers demonstrated that high EXO1 activity can produce similar molecular outcomes in cells even when the BRCA genes are functioning normally.
This finding could also have important implications for treatment. As part of the study, it was observed that olaparib, a PARP inhibitor used in BRCA-mutated cancers, is also effective in tumors with high EXO1 levels. Additionally, it was determined that these tumors are more sensitive to the widely used chemotherapy drug cisplatin. Researchers believe that in the future, similar treatment success could be achieved with lower drug doses in this patient group.
According to scientists, EXO1 could become an important biomarker that can be used in treatment planning for cancer patients in the future. If clinical trials confirm the current findings, certain targeted therapies—currently used only in patients with BRCA mutations—could be applied to a much broader group of patients. This development could contribute to the strengthening of the personalized medicine approach in cancer treatment and the development of more effective treatments tailored to patients’ genetic characteristics.
