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. 2022 Dec 6;23(23):15440. doi: 10.3390/ijms232315440

Figure 11.

Figure 11

Overview of degradation of transcription factors. (a) TRAFTAC, a heterobifunctional dsDNA/CRISPR-RNA chimera, recruits E3 ligase complex through dCas9-HT7 in the presence of HaloPROTAC. TRAFTAC binds to dCas9-HT7 via its RNA moiety while dsDNA portion of the chimera binds to the transcription factor of interest (TOI). Addition of HaloPROTAC recruits VHL E3 ligase complex to the TOI, thereby targeting it for ubiquitination and proteasomal degradation. (b) In the O-PROTAC model the dsDNA is incorporated in the TOI binding ligand of the PROTAC. (c) A BCN-modified VHL ligand (VHLL-X-BCN) is incorporated onto an azide-modified DNA oligomer (N3-ODN) via a copper-free strain-promoted azide–alkyne cycloaddition (SPAAC) reaction, forming a TF-PROTAC to recruit the VHL E3 enzyme, thereby triggering ubiquitination and degradation of the TOI by the 26S proteasome. dsDNA: double-stranded DNA; Ub: ubiquitin.