Overall structures of E. coli RNA polymerase elongation complex harboring unnatural base pair. Credit: Juntaek Oh et al.
Researchers at UC San Diego have discovered that RNA polymerase can not only recognize but also transcribe, an artificial base pair in the same manner as natural base pairs. The findings could pave the way for novel medicines created using custom-designed proteins.
The article, published in Nature Communications, answers a longstanding question of whether or not cells can recognize and utilize artificial nucleotides to make proteins. “Considering how diverse life on Earth is with just four nucleotides, the possibilities of what could happen if we can add more are enticing,” said Dong Wang, a professor at UC San Diego. “Expanding the genetic code could greatly diversify the range of molecules we can synthesize in the lab and revolutionize how we approach designer proteins as therapeutics."
The four nucleotides that comprise DNA are adenine (A), thymine (T), guanine (G), and cytosine (C). These nucleotides always form Watson and Crick pairs in the same configuration, A-T and C-G and when a number of these pairs come together they form the double-helix structure of DNA.
“This is a remarkably effective system for encoding biological information, which is why serious mistakes in transcription and translation are relatively rare,” said Dong Wang. “As we’ve also learned, we may be able to exploit this system by using synthetic base pairs that exhibit the same geometry."
In the study, researchers utilized the Artificially Expanded Genetic Information System (AEGIS) that incorporates two new base pairs. By isolating RNA polymerase and testing their interaction with the new synthetic base pairs of AEGIS, the researchers discovered that the synthetic pairs form a geometric structure closely resembling that of the Watson and Crick geometry found in natural base pairs.
“In biology, structure determines function,” said Dong Wang. “By conforming to a similar structure as standard base pairs, our synthetic base pairs can slip in under the radar and be incorporated in the usual transcription process."
The researchers intend to now shift their focus to test if their observations are consistent with other combinations of synthetic base pairs. “There could be many other possibilities for new letters besides what we’ve tested here, but we need to do more work to figure out how far we can take it,” said Wang.