Issue Date: September 19, 2011
Reimagining life’s chemical engines
By studying damaged DNA, researchers have gained new insight about the possible predecessors of protein-bound cofactors, which help carry out the essential chemical reactions of life. They propose that in the so-called RNA world—an early period of life on Earth based on RNA instead of DNA—basic biochemistry might have been catalyzed by modified RNA building blocks, such as guanine.
The hypothesis opens up a possible different dimension to the RNA world. “We’re asking the question—what were the plausible first steps” on the road to the small-molecule helpers of protein biochemistry today? says lead researcher Cynthia J. Burrows of the University of Utah.
Burrows and graduate student Khiem Van Nguyen have observed that 8-oxo-7,8-dihydroguanine, an oxidatively damaged version of the base guanine, can mimic a flavin, a type of cofactor (J. Am. Chem. Soc., DOI: 10.1021/ja2072252). Specifically, the damaged base can catalyze the repair of another type of DNA damage—light-mediated dimerization—something a flavin-containing enzyme can also do.
The researchers think the bases found in DNA and RNA were a likely evolutionary starting point for cofactors such as flavin adenine dinucleotide, a key player in the production of the energy source adenosine triphosphate. But plausible first steps on that evolutionary journey haven’t been defined.
Flavins are effective catalysts in part because of their low redox potentials. Burrows, an expert in DNA damage, knew that 8-oxo-7,8-dihydroguanine possessed a redox potential closer to a flavin’s than to those of canonical bases. So she and Nguyen incorporated the damaged base into synthetic DNA or RNA strands that contained a nearby thymine dimer, another type of DNA damage. With exposure to ultraviolet light, the modified guanine catalyzed cleavage of the thymine dimer, thereby repairing the damage.
“I’d gotten used to the idea that any changes in the structure of DNA that could cause mutations are ‘damage’ and are bad, but that’s an outlook based on life as we know it today,” Burrows says. “I’m starting to think that chemical modifications of bases could have been very useful 4 billion years ago,” before proteins emerged, she says.
Burrows says the next steps will be to try to evolve the possible proto-flavin further in the lab, examine reaction conditions for the repair process that are more plausible for a primordial Earth, and explore reactivity of other modified bases.
“If RNA catalysis predated protein catalysis, then what predated the enzyme cofactors that endow these [protein] biopolymers with their breadth of function?” asks Steven E. Rokita, who studies nucleic acid reactivity at the University of Maryland, College Park. Burrows and Nguyen’s work “presents a fascinating challenge to those interested in prebiotic chemistry and the RNA world,” he says. Moreover, the study also finds a beneficial function for a common type of DNA damage, he adds.
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