Mutagenesis: the Dark Side of the Amazing DNA Repair Shop
Imagine a marvelous "DNA Repair Shop" where the crew could keep the beast running, no matter the pings, clicks and clacks. Sounds good at first - the old machine keeps going and going, copying DNA for a new generation - but it has a dark side. Penny Beuning, a chemical biologist at Northeastern University in Boston, knows the harm that might result when cell mechanisms slip up, and then keep on copying DNA with an error. At worst the harm can include diseases like cancer. Our cells must fix up our DNA many times a day, after the daily bruising we inflict on our genes. Many times a day our cells' most precious cargo, our genome, gets battered and scrambled - by the chemicals we eat or inhale, our exposure to the sun's ultraviolet light, even the byproducts of normal metabolism. "All of that is constantly damaging our DNA," Beuning said. "But most of us stay healthy. Our cells have a powerful way to restore the DNA information to how it was before the damage was done." At its best the repair kit is rather like a built-in "system-restore" button, which sets everything right most of the time. However, a few random mutations, accidental changes that occur when DNA is being copied, can be useful to allow cells and organisms to evolve. Beuning is an expert in a newly identified part of our DNA repair team called translesion polymerases. Many questions remain about why and how these players, named only in 2001, jump in to help with the process of copying damaged DNA. "Are these tools enzyme-specific for a certain type of damage?" Beuning asks, "Or just able to copy any crazy structure that doesn't seem to belong?" Several kinds of enzymes patrol our DNA for errors and fix some of them. They regularly scan our tangled spiral staircase called the DNA double helix, focusing mostly on the areas with genes that keep us alive, but staying alert for the slightest glitch anywhere else. Replicating damaged genes could lead to harmful outcomes beyond cancer, like the cell degeneration that occurs in Alzheimer's or Huntington's disease. Specific enzymes can jump in and rebuild the genes in a damaged stretch of the helix, and they usually succeed, or we'd soon die. How that works has been studied intensively for at least 40 years, but much is still unknown. How we fix chemical damage to the six billion units, called bases, in our DNA recipe book is a vast area of biology, one involving questions about cancer, aging and the structural changes in genes that get passed on - known as mutagenesis. What we know is, we fix enough of the glitches so that life - that is, the production of new essential proteins - can continue. Our cells' proofreaders can spot any mistake, a wrong pattern, and other enzymes can insert the correct sequence, copying it from the other side of the helix. Beuning is expanding the frontiers of research in this subfield of molecular biology. Her focus is on those vigilant proofreaders. There are more of them than was thought. Her laboratory's recent work has shown that even within a cell, multiple enzymes can compete for access to the damaged DNA. It's not entirely clear how the cell picks the winner. Meanwhile, in other circumstances, the enzymes are extremely specific. Another aspect of her work examines the structures and interactions of protein machines that make all of this possible. Beuning and her team discovered that one of the DNA-copying enzymes binds to single-stranded DNA using a highly unusual "passive" mode, which likely plays a role in how all of the different enzymes compete for the DNA. Beyond those benchmarks, Beuning is pressing on, blending chemistry with genetics and physiology in a basement lab at Hurtig Hall, the heart of chemistry at Northeastern. Early in her career, Beuning set out to learn the secrets of how cells maintain their information quality, in everything from yeast and bacteria to advanced animals, like humans. In post doctoral study at MIT, she began to examine how the errors are spotted and how our cells repair them. Beuning's journey through research itself has been far from typical. She grew up in a small town in Minnesota called Avon, which, for her, evokes Garrison Keillor's "A Prairie Home Companion." "I certainly didn't know people with Ph.D.'s," she recalls. But teachers advised her to make the leap to Macalester College in St. Paul where she studied chemistry and math. "I spent all my free time in the lab. It was the greatest thing ever." A professor told her that she could be paid to do that in graduate school. "You're joking?" she replied. Before long she was doing a doctoral dissertation in chemistry at the University of Minnesota, on transfer RNA, or tRNA, the molecules that link up an amino acid sequence with the correct information in DNA. "I wanted to learn more of the biology, to learn what I didn't know," she said. That part was filled in during her MIT post doctoral research. "I studied genetics and physiology, the new things I wanted to learn," she said, "and now I am in a position to couple genetics and biochemistry." As a first-generation college graduate, she is devoted to helping the next generation, with emphasis on recruitment and training of women in science programs. "When I look back, I see that some people encouraged me to reach as high as I can reach," she said. "That made a huge difference."
Penny Beuning's Teaching Plans
Beuning plans to develop a new interdisciplinary course for chemistry majors called "Principles of Chemical Biology," focusing on using chemistry's tools to study biology. "It will introduce new technologies and give the students, mostly chemistry juniors and seniors, a sense of the modern developments in the field," she said. That will fit in neatly with Northeastern's strong emphasis on cooperative education, in which students in the five-year undergraduate program take breaks from classes and work in a professional position where they are hired and evaluated like other employees. "It's an experiential approach to learning," Beuning said, "which is what Northeastern is all about, letting students mature as people and as scientists." She also plans to use Cottrell grant funds to supplement stipends for undergraduates who work in her labs, recreating the experiences that lifted her own excitement about research. Those students will also help design new experiments for her courses.