How RNA Polymerase II Recognizes and Transcribes Artificially Added Base Pairs

In a study published in Nature Chemical Biology, a team led by researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego revealed how yeast cell machinery interacts with unnatural base pairs, and translates them into RNA. The scientists also discovered that the enzyme RNA polymerase II recognizes and transcribes artificially added base pairs in genetic code, a new insight that may help advance the development of new therapeutics

"Now we can see exactly how eukaryotic cell machinery interacts with unnatural base pairs, but it's not perfect, there's room to improve in terms of selectivity and efficiency," said senior author Dong Wang. "It's our hope that this finding will have a profound impact in the field by enabling the design of more effective, next-generation unnatural base pairs."

Wang's lab has long studied RNA polymerase II, an essential enzyme found in every fungal, plant and animal cell. RNA Pol II reads the DNA recipe and helps convert the genetic code into messenger RNA. In the past, the team has studied the structure of RNA Pol II and how it responds to normal genetic recipe hiccups such as DNA damage caused by radiation.

In their latest study, Wang's team revealed for the first time step-by-step what it looks like, structurally speaking, when eukaryotic RNA Pol II picks up and incorporates unnatural base pairs as it transcribes a piece of DNA. In doing so, they discovered, for example, that RNA Pol II is selective —it can bind X or Y on one strand of a double-stranded DNA genome, but not the other. "What we have now is a unique view of what is and what is not well recognized by RNA Pol II," said Wang. "This knowledge is important for us to design new unnatural base pairs that can be used by host RNA polymerases."