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Transcription Factors


  1. Transcription Factors Overview
  2. Transcription Factors

    Transcription factor (TF) (or sequence-specific DNA-binding factor) controls the rate of transcription of genetic information from DNA to messenger RNA. They work alone or with other proteins in a complex by binding to a specific DNA sequence to promote (as an activator), or block (as a repressor) the recruitment of RNA polymerase to specific genes. Thus, the function of TFs is to regulate (turn on and off) genes to make sure that they are expressed rightly throughout the life of the cell. The complex work of TFs coordinates with others to manipulate cell division, cell growth, and cell death throughout life; cell migration and organization (body plan) during embryonic development; and intermittent response to signals from outside the cell, such as a hormone.

    TFs contain at least one DNA-binding domain (DBD), which attaches to a specific sequence of DNA adjacent to the genes that they regulate. TFs are grouped into classes based on their DBDs, mainly including Helix-turn-Helix, Helix-Loop-Helix Zinc finger and leucine zipper proteins.

  3. Structure of Transcription Factors
  4. The structure of transcription factors consists of DNA-binding domain (DBD), trans-activating domain (TAD), and

    optional signal-sensing domain (SSD). DBD attaches to specific sequences of DNA (such as an enhancer or promoting sequences) adjacent to regulated genes. TAD contains binding sites for transcription coregulators (proteins) to activate the transcription process. SSD (e.g., a ligand binding domain) senses external signals and transmits these signals to the rest of the transcription complex, resulting in up- or down-regulation of gene expression.

    Transcription Factors

    Figure 1. The modular structure of TFs

  5. Helix-turn-Helix
  6. The helix-turn-helix (HTH) incorporates two α helices to recognize and bind DNA. It is a major structural motif capable of binding DNA in its major groove through a series of hydrogen bonds and various Van der Waals interactions with exposed bases. One of the helices is located at the N-terminal end of the motif, the other at the C-terminus. In most cases, the second helix in C-terminus contributes most to DNA recognition, and hence it is often called the "recognition helix". The other α helix in N-terminal stabilizes the interaction between protein and DNA.

  7. Helix-Loop-Helix
  8. Basic helix-loop-helix (bHLH) plays an important role in development or cellular activity. It is one of the largest families of dimerizing transcription factors. Many bHLH transcription factors are heterodimeric and their activity is often highly regulated by the dimerization of the two subunits.

  9. Zinc finger
  10. Zinc finger coordinates with one or more zinc ions (Zn2+). Proteins that contain zinc fingers (zinc finger proteins) are classified into several different structural families. Each type of zinc finger has a unique three-dimensional architecture and its class is determined by this three-dimensional structure. The majority function of Zinc finger is to bind DNA, RNA, proteins, or other small, useful molecules.

  11. β-sheet
  12. The β-sheet (also β-pleated sheet) is another common motif of secondary structure in proteins. It consists of beta strands (also β-strand) connected laterally by at least two or three backbone hydrogen bonds.

  13. leucine zipper proteins
  14. The Basic Leucine Zipper Domain (bZIP domain) is one of the largest families of dimerizing TFs. It is found in many DNA binding proteins and in all eukaryotes. It comprises a number of basic amino acids such as arginine and lysine and contains a region that mediates sequence-specific DNA binding properties.

    Transcription Factors

    Figure 2. Examples of transcription factors.

  15. Clinical Significance of Transcription Factors
  16. Transcription factors are universally involved throughout the life of the cell. Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases are associated with mutations in transcription factors. Many transcription factors are either tumor suppressors or oncogenes, and, thus, mutations or aberrant regulation of them is associated with cancer.

    A major part of currently targeted drugs directly targets the transcription factors. Examples include various types of anti-inflammatory steroids, tamoxifen for the treatment of breast and bicalutamide for the treatment of prostate cancer.

    Gene modulation is another method to target transcription factors for disease therapy. It refers to changing the expression of a gene to alleviate some form of ailment. It differs from the traditional gene therapy by targeting stoichiometrically-expressed spliced transcript variants instead of only one transcript. Modulation of gene expression can be mediated by various methods, including DNA-binding agents, synthetic oligonucleotides or small molecules.

    Designer zinc-finger proteins have undergone some trials in the clinical arena. EW-A-401, an engineered zinc-finger transcription factor has been used as a pharmacologic agent for treating claudication (a cardiovascular ailment). Investigations have been conducted in clinical trials to test efficacy and safety. This protein consists of an engineered plasmid DNA that prompts the patient to produce an engineered transcription factor to target the vascular endothelial growth factor-A (VEGF-A) gene. Two Phase I clinical studies have shown the potency as a promising and safe potential therapeutic agent for treatment of peripheral arterial disease in humans, although it has not been approved  by the U.S. Food and Drug Administration (FDA).

References:

  1. Vivekanand P et al. Lessons from Drosophila Pointed, an ETS family transcription factor and key nuclear effector of the RTK signaling pathway. Genesis. 2018 Oct 14.
  2. Grimley E et al. Are Pax proteins potential therapeutic targets in kidney disease and cancer? Kidney International. doi:10.1016/j.kint. 2018.01.025

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