Mount St. Mary's professor earns byline in top scientific journal

An article in Nature, one of the world’s top academic publications, is considered a career-building accomplishment for any researcher. Patrick Lombardi achieved that goal faster than many of his peers when his work was published in the journal earlier this month.

Lombardi — now an assistant professor of chemistry at Mount St. Mary’s University — conducted his research as a postdoctoral fellow at Johns Hopkins University, studying ubiquitin in the lab of prominent researcher Cynthia Wolberger.

A signaling protein, ubiquitin plays an important role in transmitting messages inside the cell. They also play a prominent part in the Nature article, which examined their role in repairing a common type of DNA defect known as alkylation damage.

“What we found is that to mark the site of this damage, there’s a chain of proteins — ubiquitins — that’s built and tethered in proximity to it,” said Lombardi, who worked on the paper alongside researchers from the Washington University School of Medicine in St. Louis, Missouri. “So, this is kind of the flare on the side of the road that says, ‘We need help. Something’s gone wrong.’”

Alkylation damage, specifically, can cause lesions on strands of DNA, preventing the bases from pairing properly. But what’s more important to understand, Lombardi said, is that any type of DNA damage can impede its ability to convey instructions that keep the cell functioning properly. That’s why it’s so important for the damage to be repaired quickly, ensuring that the mutations aren’t replicated.

Nima Mosammaparast, an assistant professor of pathology and immunology at Washington University, first identified ubiquitin as an important signal in repairing alkylation damage. His lab then reached out to Wolberger’s team at Johns Hopkins to collaborate on studying the interaction between ubiquitin and other components of DNA repair.

Wolberger and Lombardi found that a protein called ASCC2 recognizes the ubiquitin chain and drags other proteins over to the site of damage. That group includes another protein called ASCC3, which unwinds the helix structure, and ALKBH3, which changes the base back to its normal form.

“Essentially, with alkylation damage, atoms in part of your DNA sequence become rearranged,” said Wolberger, who’s also listed as an author on the paper. “And then those rearranged parts of the DNA need to be removed and replaced with the correct sequence.”

If the damage can’t be repaired quickly, there are often consequences for human patients. In the Nature article, researchers identified a certain enzyme mutation that prevents ubiquitin chains from forming at sites of alkylation damage. It’s an incredibly rare syndrome, Mosammaparast said — just three or four patients around the world are known to have it — but all have been diagnosed with progeria, a condition that causes rapid aging.

“So, the idea is that if you can’t repair your DNA faster, you tend to age faster, which makes sense,” Mosammaparast said.

Understanding the signaling for DNA damage is also becoming increasingly important in the field of cancer research, Lombardi said. If those signals aren’t sent, DNA mutations can quickly cause cellular alterations that can lead to cancer. One famous example is mutation of the BRAC1 gene, which creates important cancer suppression proteins. When those proteins aren’t made or don’t function correctly, the risk of some cancers grow exponentially.

About 55 to 65 percent of all women who inherit a BRAC1 mutation — like Angelina Jolie — will develop breast cancer by age 70, compared to 12 percent of women in the general population.

“When you can’t correct DNA damage, your genetic information is compromised,” Lombardi said. “It makes you more susceptible to unregulated cell proliferation and tumorigenesis.”

The study could also have important implications for alkylation chemotherapy, a common form of cancer treatment that works by introducing alkylating agents to cancer cells in order to damage their DNA and, eventually, kill them. Some tumors are less responsive to alkylation chemotherapy because they’re able to sense that damage and repair it quickly.

“We’ve seen that there are certain tumors which are resistant because they have machinery that’s important for sensing the damage,” Mosammaparast said. “Some tumor cells already have a greater ability to mount this response to alkylation damage than normal cells do. And that can be quite sad for a patient because it may mean that alkylation therapy won’t work.”

Understanding how alkylation damage is repaired, though, could lead to more targeted therapies, he added.

“We’ve found that there are a lot of molecules involved that are potential drug targets,” Mosammaparast said. “If we find a way to inhibit that repair machinery, it could make this form of chemotherapy more effective.”