Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras
| Autor: | Scott A. Holley, Dhanusha A. Nalawansha, Michael Burgess, Adrian Bebenek, Katherine Dai, Craig M. Crews, Kusal T. G. Samarasinghe, Zhenyi Hu, Saul Jaime-Figueroa |
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| Rok vydání: | 2021 |
| Předmět: |
Brachyury
Protein family Clinical Biochemistry Oligonucleotides 01 natural sciences Biochemistry Drug Discovery Animals Humans Molecular Biology Transcription factor Zebrafish Cells Cultured Pharmacology Binding Sites biology 010405 organic chemistry Oligonucleotide biology.organism_classification 0104 chemical sciences Ubiquitin ligase Cell biology DNA-Binding Proteins HEK293 Cells Proteasome biology.protein Molecular Medicine Signal transduction Transcription Factors |
| Zdroj: | Cell chemical biology. 28(5) |
| ISSN: | 2451-9448 |
| Popis: | Summary Many diseases, including cancer, stem from aberrant activation or overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity can be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription factor degradation. We show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription factor of interest (TOI) and to HaloTag-fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-κB and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins. Thus, TRAFTAC technology is potentially a generalizable strategy to induce degradation of other transcription factors both in vitro and in vivo. |
| Databáze: | OpenAIRE |
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