Zinc finger protein transcription factor

Zinc finger protein transcription factors or ZFP-TFs, consisting of activators and repressors are transcription factors composed of a zinc finger protein domain (ZFP) and any of a variety of transcription-factor effector-domains which exert their modulatory effect in the vicinity of any sequence to which the ZFP domain binds.cite journal |author=Gommans WM, Haisma HJ, Rots MG |title=Engineering zinc finger protein transcription factors: the therapeutic relevance of switching endogenous gene expression on or off at command |journal=J. Mol. Biol. |volume=354 |issue=3 |pages=507–19 |year=2005 |pmid=16253273 |doi=10.1016/j.jmb.2005.06.082 |url=http://www.rug.nl/farmacie/onderzoek/basiseenheden/therapeuticgenemodulation/publicaties/publicaties2004/2005_6.pdf]

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 which is common to multiple (usually functionally related) genes in order to control the transcription of all these genes with a single transcription factor. Alternatively, it is possible to target a family of related genes by targeting and modulating the expression of the endogenous transcription factor(s) which 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 which bind as dimers.

Applications

By targeting the ZFP towards 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. 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.cite journal |author=Wu H, Yang WP, Barbas CF |title=Building zinc fingers by selection: toward a therapeutic application |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=2 |pages=344–8 |year=1995 |pmid=7831288 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7831288] Besides the obvious development of tools for the research of gene function, engineered ZFP-TFs have enormous therapeutic potential including correction of abnormal gene expression profiles (e.g. erbB-2 overexpression in human adenocarcinomascite journal |author=Beerli RR, Dreier B, Barbas CF |title=Positive and negative regulation of endogenous genes by designed transcription factors |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=4 |pages=1495–500 |year=2000 |pmid=10660690 |doi=10.1073/pnas.040552697 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10660690] cite journal |author=Beerli RR, Segal DJ, Dreier B, Barbas CF |title=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 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=25 |pages=14628–33 |year=1998 |pmid=9843940 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9843940] and anti-retrovirals (e.g. HIV-1cite journal |author=Segal DJ, Gonçalves J, Eberhardy S, "et al" |title=Attenuation of HIV-1 replication in primary human cells with a designed zinc finger transcription factor |journal=J. Biol. Chem. |volume=279 |issue=15 |pages=14509–19 |year=2004 |pmid=14734553 |doi=10.1074/jbc.M400349200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14734553] ).

See also

*Artificial transcription factor, of which the ZFP-TF is a type
*Zinc finger chimera
*Zinc finger protein
*Zinc finger nuclease
*Gene therapy

References