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Unique change in protein structure guides production of RNA from DNA

SAN FRANCISCO, CANovember 7, 2013One of biology's most fundamental processes is something called transcription. It is just one step of many required to build proteinsand without it life would not exist. However, many aspects of transcription remain shrouded in mystery. But now, scientists at the Gladstone Institutes are shedding light on key aspects of transcription, and in so doing are coming even closer to understanding the importance of this process in the growth and development of cellsas well as what happens when this process goes awry.


"This so-called 'polymerase pausing' occurs when RNAPII literally stops soon after beginning transcription for a short period before starting up again," explained Dr. Ott, who is also a professor of medicine at the University of California, San Francisco, with which Gladstone is affiliated. "All we knew was that this behavior was important for the precise transcription of DNA into RNA, so we set out to understand how, when andmost importantlywhy."



"Our next breakthrough occurred when we pinpointed the precise locations on the CTD where acetylation occurredand realized it was unique to higher eukaryotes," explained Sebastian Schrder, PhD, the paper's first author. "We then wanted to see how this mammalian-specific acetylation fit into the realm of polymerase pausing."


"RNAPII binds to DNA to prepare for transcription. Shortly after that we see polymerase pausingat which point the CTD becomes highly acetylated," continued Dr. Shrder. "Soon after the pause, CTD is then deacetylatedthe original modification is reversedand transcription continues without a hitch."

Polymerase pausing is not unique to mammalsin fact it was characterized in HIV, the virus that causes AIDS, many years agobut the fact that the CTD becomes acetylated just before or during the time when transcription is paused appears to be unique. Drs. Ott and Schrder argue that CTD acetylation is a stabilizer, preparing RNAPII for efficient completion of transcription and slowing down the process to make sure everything is functioning correctlynot unlike the final 'systems check' a pilot must perform before takeoff.

These findings offer important insight into the relationship between acetylation and transcription. And given the importance of transcription in the growth and maturation of cells in general, the team's result stands to inform scientists about a variety of cellular processes. These include, for example, the mechanisms behind stem-cell development and what happens when normal cellular growth spirals out of control, such as in cancer.

"However, there is still much we don't know about acetylation as it relates to transcription," said Dr. Ott. "For example, if CTD acetylation is important for stabilizing transcriptional pausing, why do we also see CTD acetylation at non-paused genes, although at different locations? Further, we believe there may be other steps in the transcription cycle that depend upon acetylation. Our most immediate goal is to find them. By doing so, we hope to deepen our understanding of one of nature's most elegant biological processes."


Contact: Anne Holden
Gladstone Institutes

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