"Proteins in the bromodomain and extraterminal domain (BET) family, which include BRD2, BRD3, BRD4 and BRDT, play a crucial role in the transcription of RNA polymerase II, a multiprotein complex that travels along DNA and synthesizes RNA as the template. Small-molecule inhibitors that block interactions between BET and acetylated histone proteins have recently been developed as potential targeted therapies for many diseases, including cancer, but have not been successful in clinic."
"The findings have the potential to inform more effective targeted therapeutic approaches for many diseases, including cancer, according to said Ali Shilatifard, PhD, the chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics, who was senior author of the study. Bin Zheng, PhD, a Feinberg fellow in the Department of Biochemistry and Molecular Genetics, was the lead author of the study."
"Dr. Bin Zheng has made a major discovery in turning the pharmacology of transcriptional regulation through the BET domain protein on its head and is really mechanistically defining what these pathways are to move the field forward," said Shilatifard, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University."
New mechanisms underlying transcriptional initiation and elongation control that support proper gene expression were identified. The work links functional roles of BET family proteins (BRD2, BRD3, BRD4, BRDT) to RNA polymerase II transcription and clarifies how interactions with acetylated histones influence polymerase activity. Small-molecule inhibitors that block BET–acetylated histone interactions have been developed but have not succeeded clinically. Prior findings showed BRD4 does not require bromodomains for transcriptional elongation. The new mechanistic insights provide targets and conceptual frameworks that could enable more effective targeted therapeutic approaches for multiple diseases, including cancer.
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