Zinc finger transcription factor

Zinc finger transcription factors or ZF-TFs, are transcription factors composed of a zinc finger-binding domain and any of a variety of transcription-factor effector-domains that exert their modulatory effect in the vicinity of any sequence to which the protein domain binds.[1]

Zinc finger protein transcription factors can be encoded by genes small enough to fit a number of such genes into a single vector, allowing the medical intervention and control of expression of multiple genes and the initiation of an elaborate cascade of events.

In this respect, it is also possible to target a sequence that is common to multiple (usually functionally related) genes in order to control the transcription of all these genes with a single transcription factor. Also, it appears to be possible to target a family of related genes by targeting and modulating the expression of the endogenous transcription factor(s) that control(s) them. They also have the advantage that the targeted sequence need not be symmetrical unlike with most other DNA-binding motifs based on natural transcription factors that bind as dimers.[ibid)

Concretely

By targeting the ZF-TF toward a specific DNA sequence and attaching the necessary effector domain, it is possible to downregulate or upregulate the expression of the gene(s) in question while using the same DNA-binding domain.[2]

The expression of a gene can also be downregulated by blocking elongation by RNA polymerase (without the need for an effector domain) in the coding region or alternatively, RNA itself can also be targeted.[1][3]

Besides the obvious development of tools for the research of gene function, engineered ZF-TFs have enormous therapeutic potential including correction of abnormal gene expression profiles (e.g., erbB-2 overexpression in human adenocarcinomas)[4][5] and anti-retrovirals (e.g. HIV-1[6]).

Conclusion

For many of the genes encoding proteins involved in the transport, storage, and function of the trace elements, expression is regulated by the availability of the elements concerned. This control is exercised through a variety of mechanisms, including metal-activated transcription factors, modified usage of stop codons, and use of secondary structure within mRNA to regulate its translation and stability.

Two widely represented groups of transcription factors, often classed as zinc-finger proteins, depend on constituent zinc ions for their activity. For growth, maintenance and fetal development,  zinc can be critical in the  gene expression. (See the file on Zinc deficiencies, where the viewer learns how to be sure to have enough zinc).

Educational Video

References

  1. Gommans WM, Haisma HJ, Rots MG (2005). “Engineering zinc finger protein transcription factors: the therapeutic relevance of switching endogenous gene expression on or off at command” (PDF). J. Mol. Biol. 354 (3): 507–19. doi:10.1016/j.jmb.2005.06.082. PMID 16253273.
  2. ^ Beerli R, Barbas CF (2002). “Engineering polydactyl zinc-finger transcription factors”. Nature Biotechnology. 20 (2): 135–141. doi:10.1038/nbt0202-135. PMID 11821858.
  3. ^ Wu H, Yang WP, Barbas CF (1995). “Building zinc fingers by selection: toward a therapeutic application”. Proc. Natl. Acad. Sci. U.S.A. 92 (2): 344–8. doi:10.1073/pnas.92.2.344. PMC 42736. PMID 7831288.
  4. ^ Beerli RR, Dreier B, Barbas CF (2000). “Positive and negative regulation of endogenous genes by designed transcription factors”. Proc. Natl. Acad. Sci. U.S.A. 97 (4): 1495–500. doi:10.1073/pnas.040552697. PMC 26462. PMID 10660690.
  5. ^ Beerli RR, Segal DJ, Dreier B, Barbas CF (1998). “Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular building blocks”. Proc. Natl. Acad. Sci. U.S.A. 95 (25): 14628–33. doi:10.1073/pnas.95.25.14628. PMC 24500. PMID 9843940.
  6. ^ Segal DJ, Gonçalves J, Eberhardy S, et al. (2004). “Attenuation of HIV-1 replication in primary human cells with a designed zinc finger transcription factor”. J. Biol. Chem. 279 (15): 14509–19. doi:10.1074/jbc.M400349200. PMID 14734553
Disclaimer. Nothing in this educational post should be construed as medical or legal advise.
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