Jennifer A. Doudna
“Understanding how RNA molecules carry out chemical reactions may help us make connections between an earlier, primordial RNA world and what we see in modern biology,” says Howard Hughes Medical Investigator Jennifer A. Doudna, who on May 6 will deliver the 19th Pfizer Lecture in Memory of Konrad Bloch.
Doudna’s talk, called “Of Motions and Metals, Diverse Catalytic Strategies of Natural Ribozymes,” will show how her appreciation for these surprising RNA molecules has evolved since she completed her Ph.D. at Harvard in 1989. Although Tom Cech and Sidney Altman won that year’s Nobel Prize in Chemistry for their discovery of the first ribozymes, most scientists saw these molecules as one-trick ponies. Because negatively charged ribozymes were magnets for metals, ion binding was thought to be their only mechanism for catalyzing chemical reactions.
A ribozyme “shape-shifter”!
As it turns out, this idea was wrong. While it’s true that ribozymes drive some reactions by “positioning metal ions at the right place at the right time,” they have many other ways of triggering chemical reactions, says Doudna, who is now a professor of biochemistry and molecular biology at the University of California, Berkeley.
In the Bloch lecture, Doudna will describe three additional strategies her laboratory has identified in hepatitis viruses during the past decade. The first uses “chemical strain,” a tortuous twisting of viral RNA, to mark a cleavage site. In the second strategy, a specific ribozymal nucleotide serves as a “general base” that sets RNA scissors in motion by clipping off a proton. The third catalytic mechanism involves what Doudna calls “a very cool conformational change” that viral RNA must undergo to copy itself inside a host cell and form new infectious particles.
A common feature of these catalytic strategies is the remarkable ability of DNA to change its shape, and Doudna speculates that this dynamism may help explain why RNA appears more chemically versatile than DNA. This versatility, in turn, is consistent with the theory that RNA played a major role in the origin of life.
RNA’s stock is on the rise among basic and applied researchers, and new revelations about ribozymes are closely watched by those who were indifferent 20 years ago. “In the medical community, there’s increasing awareness that RNA does so many different things, in viruses and in cells, and we ignore it at our peril,” Doudna says.
If Konrad Bloch were still alive, Doudna muses, “it would be really interesting to know what he would think about catalytic RNA.”
If you would like to read more about Konrad Bloch, click here.