Wei Yang: Deciphering the Three Rs of DNA

BY JENNIFER SARGENT, NIAMS

Fifteen years ago, the scientific world was skeptical when structural biologist Wei Yang reported she had identified unexpected enzymatic activity in one of the proteins that played an essential role in maintaining genome stability. Other scientists attributed her findings to contamination during protein purification procedures.

But Yang persisted. She demonstrated adenosine triphosphatase (ATPase) activity in MutL, a key protein that corrects DNA replication errors. ATPase catalyzes a reaction that releases energy to be used in cellular metabolism. Until Yang’s discovery no one understood how MutL worked. She also showed that MutL underwent a conformational change that modulated its specificity for binding DNA and protein cofactors. Her results, although controversial, were finally published in Cell in 1998 and 1999 (Cell 95:541–552, 1998; Cell 97:85–97, 1999). This year, in recognition of all her scientific accomplishments, Yang was elected to the National Academy of Sciences.

Yang, who is a section chief in the Laboratory of Molecular Biology in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), uses X-ray crystallography and other methods to study the enzymes involved in DNA repair, recombination, and replication—the “3 Rs” of DNA maintenance. X-ray crystallography is a technique used to deduce the 3-D structure of a protein—or a protein-substrate complex—by aiming X-rays at a crystal of the macromolecule and measuring the pattern and intensity of the scattered X-rays.

In a recent presentation to the scientific directors, Yang demonstrated how 3-D structures of protein-DNA complexes provide unique insights into dynamic interactions between proteins and their substrates in health and disease. Her studies on DNA polymerase eta (Pol eta), an enzyme involved in DNA repair, have led to a better understanding of the molecular events underlying the genetic skin disorder xeroderma pigmentosum. Patients with the disorder are highly sensitive to the sun’s ultraviolet rays and are at increased risk for developing skin carcinomas.

Early in her training, Yang never imagined she would become a structural biologist. When she began her graduate work, in 1985, at Columbia University’s (New York) Department of Biochemistry and Molecular Biophysics, she had every intention of studying oncogenes and gene regulation. But during a rotation in a biophysics lab, one of her professors described structural biology as “molecular biology in three dimensions.” These words stuck a chord with Yang and she shifted her doctoral studies from gene hunting to molecular biophysics.

In 1992, Yang joined Thomas Steitz’s lab at Yale University (New Haven, Conn.). (Steitz shared the Nobel Prize in Chemistry in 2009 for studies of the structure and function of the ribosome). Yang wanted to examine the mechanisms of recombination activating gene (RAG)–mediated V(D)J recombination, the process by which antibodies and receptors are assembled in the immune cells. But she was ahead of her time—the tools needed for such studies were underdeveloped—and Steitz discouraged her from embarking on the project. Instead, she focused her structural efforts on gamma delta resolvase, an enzyme involved in DNA recombination in bacteria.

When Yang came to NIDDK in 1995 as an independent investigator, she was impressed with the collaborative environment of the NIH intramural community. “I knew that I just had to be here,” she said. She has since collaborated on many projects with NIH intramural investigators. She even had the opportunity to revisit her fascination with understanding V(D)J recombination by working with Martin Gellert (NIDDK) (http://www2.niddk.nih.gov/NIDDKLabs/IntramuralFaculty/GellertMartin.htm).

Among Yang’s other collaborators are Robert Crouch (https://irp.nih.gov/pi/robert-crouch), at the National Institute of Child Health and Human Development, and Stuart Le Grice (http://ccr.cancer.gov/staff/staff.asp?profileid=5552), at the National Cancer Institute. Their structural work provides insights into the molecular mechanism for HIV resistance in a broad range of antiretroviral therapy drugs. Yang hopes their work will lead to the development of novel anti-HIV therapeutics.

Yang’s work goes beyond determining the 3-D nature of protein structures. By studying the 3Rs of DNA metabolism, she has contributed to our knowledge of enzymes that bind to and process DNA and extended these findings to clinical applications. For example, the same gene that is mutated in patients with xeroderma pigmentosum directs the production of an enzyme that interferes with a chemotherapy drug that kills cancer cells. Yang and her colleagues are using their knowledge of the structure and function of Pol eta to develop inhibitors that could increase the efficiency of anticancer drugs.

And so Yang returns to her roots—oncogenes and gene regulation—but now with a 3-D view.

TO READ MORE ABOUT YANG’S RESEARCH, VISIT HER WEB SITE AT http://www-mslmb.niddk.nih.gov/wei/yanggroup.html.

Wei Yang will be also presenting her work at the Anita Roberts Lecture on Tuesday, September 17, 2013, 1:00-2:00 p.m., Lipsett Amphitheater (Building 10). See announcements.