PUBLICATION
Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras
- Authors
- Samarasinghe, K.T.G., Jaime-Figueroa, S., Burgess, M., Nalawansha, D.A., Dai, K., Hu, Z., Bebenek, A., Holley, S.A., Crews, C.M.
- ID
- ZDB-PUB-210410-12
- Date
- 2021
- Source
- Cell chemical biology 28(5): 648-661.e5 (Journal)
- Registered Authors
- Holley, Scott
- Keywords
- E3 ligase, HaloTag, PROTACs, brachyury, dCas9, degradation, proteasome, transcription factors, undruggable, zebrafish
- MeSH Terms
-
- Animals
- Binding Sites
- Cells, Cultured
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/metabolism
- HEK293 Cells
- Humans
- Oligonucleotides/metabolism*
- Transcription Factors/metabolism*
- Zebrafish
- PubMed
- 33836141 Full text @ Cell Chem Biol
Citation
Samarasinghe, K.T.G., Jaime-Figueroa, S., Burgess, M., Nalawansha, D.A., Dai, K., Hu, Z., Bebenek, A., Holley, S.A., Crews, C.M. (2021) Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell chemical biology. 28(5):648-661.e5.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping