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Novel mechanism eliminates 'bad' enzyme during gene expression

Northwestern Medicine investigators have discovered a novel mechanism that recognizes and eliminates "bad" transcriptional elongation enzymes during gene expression, findings that may inform the understanding of adrenal diseases, according to a recent study in Science Advances.

Ali Shilatifard, Ph.D., the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics, was senior author of the study.

The process of transcription elongation by RNA polymerase II (Pol II), in which Pol II travels along DNA and synthesizes RNA from DNA, is essential for proper gene expression in all eukaryotic cells.

Previous work from the Shilatifard laboratory had demonstrated that the protein SPT5 serves as a checkpoint in this process. With SPT5, Pol II is allowed to travel down the length of DNA. When SPT5 is lost, however, Pol II is instead degraded and destroyed. The protein that recognizes Pol II for degradation had remained unknown, however.

Using an unbiased proteomic screening and genome-wide analysis, the investigators discovered that the ARMC5 protein recognizes Pol II when SPT5 is lost and forces Pol II to enter a "noncanonical early termination pathway," in which Pol II is ultimately degraded.

"With this mechanism, we now understand how the cells eliminate a bad transcription complex," said Yuki Aoi, Ph.D., assistant professor of Medicine and of Biochemistry and Molecular Genetics, who was first author of the study. "When SPT5 is lost, this ARMC5 mechanism will recognize RNA polymerase II and then eliminate this defective transcription complex."

The findings may also inform the understanding of the development of certain diseases, according to Aoi. For example, ARMC5 mutations are known to cause adrenal hypoplasia, a type of adrenal disorder that prevents proper development of the adrenal glands and causes hormone imbalances.

"Even though we don't know how these mutations of ARMC5 cause the disease, our findings can help us better understand what the exact function of ARMC5 is," Aoi said.