A Biologist’s Quest to Unlock the Mysteries of DNA Damage

Fruit flies have a lot in common with humans. Those similarities help Mitch McVey, professor of biology in the School of Arts and Sciences and the Graduate School of Biomedical Sciences, and his colleagues unearth clues to better treatments for inherited forms of cancers that become resistant to current therapies. And the similarities also suggest ways clinicians might one day prevent the slight increase in congenital disorders seen in babies whose mothers take antidepressants during pregnancy.

“Fruit flies have 60–70% of the same DNA as humans,” McVey said. “They enable us to focus on what happens in entire organisms and get better answers than working only with cells.”

Cancer Trials

Cancer develops when DNA mutations cause cells to multiply uncontrollably. But the DNA of cancer cells also tends to break and mutate, so in order for those cancer cells to proliferate, they must be able to repair their DNA. Cancers driven by defects in BRCA1 and BRCA2 genes rely on one particular pathway, called alternative end joining, to fix their broken DNA. Fruit flies rely heavily on that same pathway.

Earlier in his career, McVey and colleagues identified a protein called DNA polymerase theta that plays a primary role in alternative end joining in fruit flies. That discovery may hold the key to treating cancers caused by BRCA1 and BRCA2 gene defects, most commonly associated with certain forms of breast and ovarian cancer. Scientists in other labs have since identified small molecules that target DNA polymerase theta. Proven effective in animal models, those small molecules are now being tested as a possible treatment for people.

Antidepressants and Pregnancy

Fruit fly larvae grow very rapidly, as does a human fetus in its earliest stages. Research by McVey and Michael Levin, the Vannevar Bush Professor of Biology, and undergraduate students revealed that when fruit fly larvae are bathed in the antidepressant sertraline (brand name Zoloft), almost half do not survive. Those that do develop more slowly and have three times the normal number of double-stranded DNA breaks in developing wings, suggesting that sertraline might contribute to congenital disorders by directly damaging the genetic code of the embryos.

This result had not previously been seen in human cells grown in the lab or in mice. The researchers hypothesized the cause might be oxidative stress, a state where too many unstable molecules—called free radicals—are present, with insufficient antioxidants available to inhibit the potential for damage. The researchers discovered that when the larvae were fed both sertraline and the powerful antioxidant vitamin C, almost all survived, and there were far fewer DNA breaks.

The researchers’ next goal is understanding if and how sertraline is interacting with DNA to cause damage. “The results are interesting, but we need more research before anyone is going to recommend that pregnant women take lots of vitamin C—no matter how innocuous it might seem—to decrease the small risk of congenital disorders that has been suggested to be associated with sertraline,” McVey cautioned.

Stress and DNA Damage

McVey has worked with fellow biology professor Michael Romero and graduate students to study whether measuring DNA damage might also be a way to assess the effects of stress on health and disease. Studies of wild birds experiencing stressors of captivity showed that the birds’ red blood cells developed both short- and long-term DNA damage. McVey said the question is whether the stress causes oxidative damage—“a bad thing”—or whether the cells are trying to adapt as part of a positive stress response.

The work opens important new pathways for understanding how stress may lead to DNA damage and repair, and whether that process might be targeted to improve health.