Overactive DNA repair gene may flag tumors for targeted drugs
Penn State researchers say excess EXO1 can damage DNA and make some tumors respond like BRCA-mutant cancers.
By Priya Raghavan · Science Reporter
3 min read
Penn State researchers have found that a DNA repair gene can harm cells when it is produced at abnormally high levels. The finding matters because tumors with excess EXO1 may be vulnerable to drugs now used for BRCA-mutant cancers, according to a study published in Nature Communications.
The team reported that EXO1, a gene normally involved in DNA maintenance, can destabilize the genome when overexpressed. Penn State said elevated EXO1 appears in 20% to 30% of breast and ovarian cancers and also shows up in melanoma, testicular, cervical and hepatobiliary cancers.
George-Lucian Moldovan, a professor of molecular and precision medicine at Penn State College of Medicine and the study’s senior author, said EXO1 is not a marker of inherited cancer risk. He said it could instead help identify patients whose tumors are more likely to respond to certain treatments.
“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,” Moldovan said, according to Penn State.
How the gene causes damage
The researchers analyzed tumor data from The Cancer Genome Atlas, a National Cancer Institute cancer genomics program, and found evidence of EXO1 overproduction across several cancer types, Penn State said. The association was especially strong in basal-like breast cancer, described by the university as an aggressive form of the disease.
In laboratory work using commercially available human cancer cells, the team increased EXO1 production to study its effect on DNA. The researchers also built an inactive form of the protein, which let them test whether DNA damage came from EXO1’s biochemical activity rather than from the protein’s presence alone.
Under typical conditions, EXO1 helps trim DNA as part of repair. When cells make too much of it, Penn State said, EXO1 starts cutting or degrading DNA structures that should be protected.
The study found that excess EXO1 harms newly made DNA in two ways: by expanding single-stranded DNA gaps and by degrading reversed replication forks. Moldovan said those processes produce localized genetic loss and DNA instability.
Alexandra Nusawardhana, the study’s lead author and a recent Penn State biomedical sciences doctoral graduate, said the damage can include double-strand breaks. She said the resulting DNA lesions may help explain why the affected tumor cells become more sensitive to chemotherapy and die at higher rates.
Why it resembles BRCA-mutant cancer
BRCA genes normally help protect DNA during replication, according to Penn State. When BRCA genes are mutated, cells lose part of that protection, a defect tied to hereditary breast and ovarian cancer risk.
The Penn State team found that cells with high EXO1 activity behaved like BRCA-mutant cells even when their BRCA genes were intact. The researchers also reported that EXO1 works with another protein, MRE11, to widen DNA gaps and create harmful breaks.
“Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells,” Moldovan said.
Treatment implications
Because of that similarity, the researchers tested whether EXO1-overexpressing tumors would respond to olaparib, a drug used against BRCA-mutant cancers that targets DNA repair pathways. Penn State said the tumors were highly sensitive to the drug and responded in a way similar to BRCA-mutant tumors.
The team also found that tumors with elevated EXO1 responded to cisplatin, a widely used chemotherapy drug. Penn State said the results raise the possibility that lower cisplatin doses could produce comparable tumor shrinkage while reducing side effects, though that would require further study.
The researchers plan to continue studying EXO1 with the long-term goal of clinical trials in patients whose tumors overexpress the gene. Penn State said Claudia Nicolae, an assistant professor of molecular and precision medicine, also contributed to the work, which was funded by the National Institutes of Health and Four Diamonds.
This story draws on original reporting from ScienceDaily.