Stress Triggers Key Molecule to Halt Transcription of Cell’s Genetic Code

For almost three decades, investigators Joan Conaway, PhD, and Ronald Conaway, PhD, have studied the fundamental mechanisms that drive transcription, the first step in gene expression.

Many of their discoveries have focused on elongin A, a molecule that plays two roles in this process — acting as a facilitator by restarting transcription machinery when it sputters or a destroyer by marking the transcription machinery to be decommissioned when it is stalled.

In a study led by the Conaways, researchers at the Institute and at Kochi Medical School in Japan have now discovered how elongin A morphs between these two identities. It was previously known that as a facilitator, elongin A partners with its sister proteins elongin B and C, and as a destroyer, it also brings in another protein, Cul5, to form a complex known as ubiquitin ligase. Juston Weems, PhD, a postdoctoral researcher and first author of the study, decided to track and monitor this elongin A-Cul5 association in healthy and stress-induced cells. By fluorescently tagging the proteins, Weems and colleagues found that the complex not only rapidly accumulated in response to localized DNA damage that is known to stall polymerase, but also in response to various other stimuli that are not known to stall polymerase.

“It’s possible that the ligase forms under these circumstances just in case the polymerase gets ‘stuck’ on some critical, newly activated genes,” says Joan Conaway. “On the other hand, these results raise for the first time the possibility that elongin A might play a positive role in gene activation by some mysterious mechanism that we’d really like to understand.” Understanding whether elongin A plays a previously unexplored role in gene activation will be the next step for these researchers.

This study was published in the June 12, 2015, issue of The Journal of Biological Chemistry.