Thousands of times a day, the DNA strands inside our cells are broken. Breaks in both strands of the DNA helix can happen when cells duplicate their chromosomes, or as a consequence of oxidation or exposure to DNA-damaging radiation or chemicals. At these moments, cellular sentinels rush to the scene to repair the damage. If the repair is unsuccessful and the damage lingers, mutations can accumulate and cause cancer.

That's why Tanya Paull—the first researcher at the University of Texas at Austin to be named an HHMI investigator—has dedicated her career to understanding DNA repair. DNA is repaired by an intracellular triage system that in many ways is still mysterious. "DNA repair is the first line of defense against mutations that cause cancer," says Paull. "If we knew how a cell normally responds to damage, we would better understand how the process goes wrong in cells that develop into tumors."

Paull focuses on a complex of proteins called MRN (named for its three components, MRE11, RAD50, and NBS1). Whenever double-stranded DNA breaks occur, MRN clamps onto the frayed ends of the double helix and begins stitching it back together. Simultaneously—and just as importantly—MRN sends out a distress signal, telling other proteins to squelch the growth of the cell. "The signaling cascades that occur after DNA damage are very important," says Paull. "They tell the cell to stop growing." This prevents the damage from propagating, possibly leading to tumors.

Paull discovered MRN's signaling function through painstaking work, she says. It required the development of a system that produces MRN as well as a protein called ATM that catalyzes the signaling. The purification of these complexes was something of a biochemical tour de force, requiring long hours in the lab for Paull and her students.

Paull began to appreciate scientific questions as puzzles that needed to be solved when, as an undergraduate, she spent two years working at the Linus Pauling Institute, then affiliated with Stanford University. "I was given a lot of independence, even as an undergrad. I didn't know a lot about science at the time, but the independent nature of it was a lot of fun. I liked the process of posing a question, going to the library, searching the literature, and figuring out what to do," Paull says.

Paull learned the basics about working with DNA and became intrigued with how DNA and proteins interact during her junior year in college, which she spent at Oxford University in England. She worked in the laboratory of biochemist Paul Nurse, a current HHMI Trustee who shared the Nobel Prize in Physiology or Medicine in 2001 for his work on the cell cycle. Part of that work examined how cells regulate the process of DNA duplication. Paull's current research examines how this process is affected by the presence of DNA damage in cells, and investigates the biochemical mechanisms involved in sensing this damage.

Paull oversees 10 people in her lab—mostly graduate students—and says she relishes watching the young scientists learn and contribute. "Graduate students have done all of the work that we've published," says Paull. "So I see myself having a dual role—I'm always pushing forward with very difficult projects, but I'm also training the students so they can see how the whole process works. There's a challenge in that."

Just as there's a challenge in understanding DNA repair. While such work has obvious implications for learning how cancer develops, it has a more direct impact on a disease called ataxia telangiectasia, or A-T. In this genetic disease, which strikes about 1 in 100,000 people, cells lack the protein ATM. This protein puts the brakes on the growth of damaged cells; it's the protein that MRN hails when MRN senses DNA damage. "People with A-T are very radiation sensitive. They get cancers at an early age, and for reasons we don't really understand, they also suffer very debilitating neurological degeneration," says Paull. Likewise, there are a small number of patients with mutations in one of the MRN proteins who display the same symptoms. "This is a compelling argument that MRN and ATM are working on the same pathway," says Paull.

So now Paull is trying to understand exactly how MRN and ATM function together, hoping that such insights might one day lead to treatments for these incurable diseases.

"Our projects allow us to do very basic biochemistry, pure fundamental research into what this MRN complex is doing, but it also has some clinical relevance as well," says Paull. "This is a technically challenging area of research but it has great potential for insights into the mechanisms of DNA repair and also the pathways of tumor progresssion."